C-halogen bond formation

ABSTRACT

Methods of halogenating a carbon containing compound having an sp3 C—H bond are provided. Methods of fluorinating a carbon containing compound comprising halogenation with Cl or Br followed by nucleophilic substitution with F are provided. Methods of direct oxidative C—H fluorination of a carbon containing compound having an sp3 C—H bond are provided. The halogenated products of the methods are provided.

This application claims the benefit of U.S. Provisional Application No.61/525,301, filed Aug. 19, 2011, U.S. Provisional Application No.61/639,523, filed Apr. 27, 2012, and U.S. Provisional Application No.61/679,367, filed Aug. 3, 2012, which are incorporated herein byreference as if fully set forth.

This invention was made with government support under Grants No.CHE-0616633 and CHE-1148597 awarded by the National Science Foundationand with support from the Center for Catalytic HydrocarbonFunctionalization, an Energy Frontier Research Center funded by the U.S.Department of Energy, Office of Science, Office of Basic Energy Sciencesunder Award No. DE-SC0001298. The government has certain rights in thisinvention.

FIELD

The disclosure relates to halogenation of carbon containing compoundsand the products of halogenation.

BACKGROUND

Halogenated organic compounds play a central role in organic chemistry,affording important components of a variety of biologically activemolecules as well as pharmacologically active agents. Alkyl chloridesalso find widespread use as intermediates in organic synthesis, as incross-coupling reactions.

Manganese porphyrins and Schiff base complexes have long been known tobe effective catalysts for the oxygenation of both unsaturated andsaturated hydrocarbons. Nearly all of the advances in the field dealtwith oxygenation reactions, particularly olefin epoxidation and alkanehydroxylation. Small amounts of halogenation were described in theoriginal reports. However, most of these reactions resulted in poorselectivity for non-oxygen functionalization, since competitiveoxygenation of substrates remains the main reaction. High selectivity ofchlorination has been reported by Ricci et al. in thenickel(salen)/hypochlorite system, but the substrate scope was limitedand the reaction was likely propagated by chloroxy radical. (Querci, C.;Strologo, S.; Ricci, M. Tetrahedron Lett. 1990, 31, 6577-6580, which isincorporated herein by reference as if fully set forth). There are atpresent few if any ways to incorporate halogen atoms selectively intocomplex compounds.

Nature has found highly selective ways to transform aliphatic C—H bondsinto alcohols, halides and olefins using reactive metal-oxointermediates within enzymes. A notable exception is aliphaticfluorination, for which there are no known biochemical precedents. Thereare also no direct ways to convert unreactive sp³ C—H bonds into C—Fbonds through chemical catalysis.

Although strategies for aromatic C—H fluorination developed over thepast five years have provided novel and unprecedented access to complexaryl fluorides, (Furuya, T.; Kamlet, A. S.; Ritter, T., Catalysis forFluorination and Trifluoromethylation Nature 2011, 473, 470-477; P. P.Tang, T. Furuya, T. Ritter, J Am Chem Soc 132, 12150 (2010); and D. A.Watson et al. Science 325, 1661 (2009), which are incorporated herein byreference as if fully set forth) there is a notable lack of recentprogress for the catalytic fluorination of aliphatic C—H bonds (P.Herrmann, J. Kvicala, V. Pouzar, H. Chodounska, Collect Czech Chem C 73,1825 (2008); and Rozen, S.; Gal, C., Activating Unreactive Sites ofOrganic-Molecules Using Elemental Fluorine, J. Org. Chem. 1987, 52,2769-2779, which are incorporated herein by reference as if fully setforth). Traditional methods for introducing fluorine into a saturatedframework require harsh conditions and highly toxic fluorine sources,such as elemental fluorine, that require specialized equipment and arenot compatible with many typical substituents and functional groups (R.D. Chambers, A. M. Kenwright, M. Parsons, G. Sandford, J. S. Moilliet, JChem Soc Perk T 1, 2190 (2002); S. Rozen. Eur. J. Org. Chem., 2433(2005); and S. Rozen. Acc. Chem. Res. 38, 803 (2005), which areincorporated herein by reference as if fully set forth). Metal catalyzeddirect benzylic C—H fluorination has been achieved recently withpalladium catalysts and a source of “F⁺” (K. L. Hull, W. Q. Anani, M. S.Sanford. J. Am. Chem. Soc. 128, 7134 (2006); X. S. Wang, T. S. Mei, J.Q. Yu. J. Am. Chem. Soc. 131, 7520 (2009); T. D. Beeson, D. W. C.MacMillan. J. Am. Chem. Soc. 127, 8826 (2005), which are incorporatedherein by reference as if fully set forth). Also, advances in the fieldof enantioselective organocatalytic fluorination have been reported thatare capable of introducing a fluorine atom adjacent to a carbonyl group(T. D. Beeson, D. W. C. MacMillan. J. Am. Chem. Soc. 127, 8826 (2005),which is incorporated herein by reference as if fully set forth) and viathe ring-opening of epoxides with a fluoride nucleophile (J. A. Kalow,A. G. Doyle. J. Am. Chem. Soc. 132, 3268 (2010), which is incorporatedherein by reference as if fully set forth). A chemo-enzymaticfluorination strategy via initial P450-mediated hydroxylation (R. Fasan,A. Rentmeister, F. H. Arnold. Nat. Chem. Biol. 5, 26 (2009), which isincorporated herein by reference as if fully set forth) and astoichiometric chemical route involving initial decarboxylation (M.Rueda-Becerril et al. J. Am. Chem. Soc. 134, ASAP (2012), which isincorporated herein by reference as if fully set forth) have also beenreported. Despite this impressive progress, a method for the selectiveand efficient incorporation of fluorine at unactivated C—H sites withina target molecule is singularly absent in the repertoire of chemicalsynthesis.

SUMMARY

In an aspect, the invention relates to a method of direct oxidative C—Hfluorination of a carbon containing compound having an sp3 C—H bondcomprising combining a carbon containing compound, a fluorinating agent,a fluorinating catalyst, and an oxidant.

In an aspect, the invention relates to a composition comprising theproduct of any method herein.

In an aspect, the invention relates to a method of visualizationcomprising fluorinating a carbon containing compound having an sp3 C—Hbond by any method herein, wherein the fluorinating agent includes ¹⁸Fand a product produced by the method includes ¹⁸F to create an imagingagent, administering the imaging agent to a patient, and performingpositron emission tomography on the patient.

In an aspect, the invention relates to a composition comprising at leasttwo or more of a carbon containing compound, a fluorinating agent, afluorinating catalyst and an oxidant.

In an aspect, the invention relates to a composition comprising atrans-difluoromanganese(IV) porphyrin Mn^(IV)(TMP)F₂.

In an aspect, the invention relates to a composition comprising amanganese complex having at least one fluoride ligand bound to themanganese and the formula L₅Mn(IV)—F, where L is selected from the groupincluding oxygen, nitrogen, and halide, and the manganese has octahedralcoordination with six total ligands and a neutral overall charge.

In an aspect, the invention relates to a composition comprising amanganese complex having at least one fluoride ligand bound to themanganese and the formula L₅Mn(V)—F, where L is selected from the groupconsisting of oxygen, nitrogen and halide, and the manganese hasoctahedral coordination with six total ligands and a neutral overallcharge.

In an aspect, the invention relates to a composition comprising amanganese complex having one or two fluoride ligands bound to themanganese and the formula L₅Mn(IV)—F or L₄Mn(IV)—F₂, where L is selectedfrom the group consisting of oxygen, nitrogen and halide, and themanganese has octahedral coordination with six total ligands and aneutral overall charge.

In an aspect, the invention relates to a composition comprising afluoro-buspirone.

In an aspect, the invention relates to a composition comprising at leasttwo or more of a carbon containing compound having an sp3 C—H bond, afluorinating agent, a fluorinating catalyst, or an oxidant.

In an aspect, the invention relates to a kit comprising one or morecontainer, wherein each container includes at least one reactant for afluorination reaction selected from the group consisting of a carboncontaining compound, a fluorinating agent, a fluorinating catalyst, andan oxidant, wherein the composition includes at least one fewersubstance than required to make a fluorination reaction proceed.

In an aspect, the invention relates to a composition comprising aproduct of a method of direct oxidative C—H fluorination of a carboncontaining compound having an sp3 C—H bond comprising combining a carboncontaining compound, a fluorinating agent, a fluorinating catalyst, andan oxidant.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of the preferred embodiments of thepresent invention will be better understood when read in conjunctionwith the appended drawings. For the purpose of illustrating theinvention, there are shown in the drawings embodiments which arepresently preferred. It is understood, however, that the invention isnot limited to the precise arrangements and instrumentalities shown. Inthe drawings:

FIGS. 1A-1B illustrate halogenation of complex substrates. FIG. 1Aillustrates steric effects that may lead to selective chlorination of5α-cholestane at the C2 and C3 positions. NMR yields shown. FIG. 1Billustrates C2-selective chlorination of sclareolide. Isolated yieldshown.

FIGS. 2A-2D illustrate manganese porphyrin catalyzed selective C—Hfluorination of complex molecules. In FIG. 2A, fluorination oftrans-decalin gave predominantly (41%) methylene fluorination. In FIG.2B, steric and electronic effects lead to selective 5-exo-fluorinationof bornyl-acetate (55%). In FIG. 2C, steric effects on5α-androstan-17-one lead to selective ring A fluorination (48%). In FIG.2D, selective fluorination of sclareolide is illustrated.

FIGS. 3A-3D: FIG. 3A illustrates a proposed catalytic cycle for amanganese porphyrin catalyzed C—H fluorination reaction. FIG. 3Billustrates inferred stereoelectronics for hydrogen abstraction. FIG. 3Cillustrates the molecular structure of trans-Mn^(IV)(TMP)F₂ drawn at 50%probability of the electron density. FIG. 3D illustrates selected bondlengths and angles of trans-Mn^(IV)(TMP)F₂.

FIG. 4 illustrates synthesis of trans-Mn^(IV)(TMP)F₂.

FIGS. 5A-5B: FIG. 5A illustrates the UV-vis spectrum oftrans-Mn^(IV)(TMP)F₂. FIG. 5B illustrates experimental (top) andsimulated (bottom) EPR spectra of trans-Mn^(IV)(TMP)F₂ (Detailparameters: X-band EPR (9.453 GHz) using 50/50 v/v toluene/CH₂Cl₂glasses at 10K. Modulation frequency 100 kHz, modulation amplitude 12.5G, time constant 163.84 ms, scan time 335 s, microwave power 15.9 mW,and spectrometer gain 10000).

FIG. 6 illustrates the fluorine transfer of trans-Mn^(IV)(TMP)F₂ toalkyl radical.

FIGS. 7A-7D: FIG. 7A illustrates the product of buspirone precursorfluorination. FIG. 7B illustrates that fluorination of buspironeprecursor affords fluorinated product with another unknown product. FIG.7C illustrates the mass spectrum of the fluorinated buspirone peak. FIG.7D illustrates the mass spectrum of the buspirone precursor startingmaterial.

FIG. 8 illustrates the structure of Mn(TMP)F₂.

FIGS. 9A-9B illustrate fluorination of N-Phth amantadine.

FIGS. 10A-10B illustrate fluorination of N-Phth Memantine.

FIGS. 11A-11B illustrate fluorination of 2-adamantanone.

FIGS. 12A-12B illustrate fluorination of rimantadine analogue.

FIGS. 13A-13B illustrate fluorination of adapalene precursor.

FIGS. 14A-14B illustrate fluorination of perindopril precursor.

FIGS. 15A-15B illustrate fluorination of protected gabapentin.

FIGS. 16A-16B illustrate fluorination of methyl octanoate.

FIGS. 17A-17B illustrate fluorination of methyl nonanate.

FIGS. 18A-18C illustrate fluorination of methyl hexanoate.

FIGS. 19A-19C illustrate fluorination of cyclohexyl acetate.

FIGS. 20A-20C illustrate fluorination of cyclohexane carboxylic acidmethyl ester.

FIG. 21 illustrates lyrica (pregabalin) with venlafaxin-fluorineintroduced into the cyclohexyl ring at positions C3 and C4.

FIG. 22 illustrates fluorine introduced into the secondary and tertiarypositions of the isobutyl substituent.

FIGS. 23A-23D illustrate examples of ligands that will assist C—Hfluorination. FIG. 23A illustrates a porphyrin. FIG. 23B illustratesphthalocyanine. FIG. 23C illustrates a porphyrazine. FIG. 23Dillustrates tetra-N-methyl-tetra-2-pyridoporphyrazine.

FIGS. 24A-24G illustrate examples of ligands that will assist oxidativeC—H fluorination. FIG. 24A illustratesN-Pyridylmethyl-tri-aza-cyclononane. FIG. 24B illustratesN,N-Dipyridylmethyl cyclohexadiamine. FIG. 24C illustratestetra-aza-cyclotetra-decane. FIG. 24D illustrates N,N-dipyridylmethyl2,2′-dipyrrolidine. FIG. 24E illustrates N,N-dipyridylmethylethylenediamine. FIG. 24F illustrates tripyridyl amine (TPA). FIG. 24Gillustrates salen.

FIG. 25 illustrates a manganese porphyrin-catalyzed fluorinationreaction scheme.

FIGS. 26A-26D illustrate manganese porphyrin catalyzed selective C—Hfluorinations. FIG. 26A illustrates methylene-selective fluorination oftrans-decalin. FIG. 26B illustrates selective fluorination ofsclareolide. FIG. 26C illustrates selective A ring fluorination of5α-androstan-17-one. FIG. 26D illustrates selective 5-exo-fluorinationof bornyl-acetate.

FIG. 27 illustrates an Mn^(IV)(TMP)F₂ structure.

FIG. 28 illustrates an EPR spectra of (X)₂MN^(IV)TMP complexes.

FIG. 29 illustrates a manganese salen catalyst.

FIG. 30 illustrates manganese salen catalyzed benzylic C—H fluorination.

FIG. 31 illustrates potential manganese salen catalyzed benzylic C—Hfluorination substrates.

FIG. 32 illustrates a manganese salophen complex.

FIG. 33 illustrates a manganese salen complex.

FIG. 34 illustrates trans-difluoro-manganese(IV) salen complexes.

FIG. 35 illustrates trans-difluoro-manganese(IV) salen complexes.

FIG. 36 illustrates trans-difluoro-manganese(IV) cyclohxyl-salen.

FIG. 37 illustrates trans-difluoro-manganese(IV) salophen complexes.

FIG. 38 illustrates exemplary substrates that may be used in any methodcontained herein.

FIG. 39 illustrates exemplary substrates that may be used in any methodcontained herein.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Certain terminology is used in the following description for convenienceonly and is not limiting. The words “a” and “one,” as used in the claimsand in the corresponding portions of the specification, are defined asincluding one or more of the referenced item unless specifically statedotherwise. The phrase “at least one” followed by a list of two or moreitems, such as “A, B, or C,” means any individual one of A, B or C aswell as any combination thereof.

Porphyrin catalysts and methods of use thereof are discussed in U.S.Publication No. 2011/0306584; U.S. Publication No. 20100093688; U.S.Pat. No. 6,969,707; U.S. Pat. No. 6,448,239; U.S. Pat. No. 6,002,026;and PCT/US2011/48396, which are incorporated herein by reference as iffully set forth. The embodiments described herein extend the knowledgeof porphyrin catalysts and methods of use thereof. One or more of theporphyrin catalysts in U.S. Publication No. 2011/0306584; U.S.Publication No. 20100093688; U.S. Pat. No. 6,969,707; U.S. Pat. No.6,448,239; U.S. Pat. No. 6,002,026; and PCT/US2011/48396 may be utilizedin an embodiment herein as a halogenating catalyst or a fluorinatingcatalyst.

Methods of halogenating carbon containing compounds are provided herein.An embodiment provides a method of halogenating a carbon containingcompound comprising reacting a carbon containing compound with ahalogenating agent in the presence of a halogenating catalyst and aphase transfer catalyst. A non-limiting example follows: Under anitrogen atmosphere, 2 mL sodium hypochlorite (0.33 M) was added to asolution of Mn(TMP)Cl (0.033 mmol), tetrabutylammonium chloride (TBACl,0.027 mmol), and substrate (0.22 mmol) in 1 mL dichloromethane in a 4 mLsealed vial. The biphasic mixture was stirred smoothly under nitrogen.The reaction was monitored by GC/MS or TLC and additional sodiumhypochlorite solution is added under nitrogen if the conversion of thesubstrate is low. The product was purified by flash columnchromatography. The amount of hypochlorite could be 1-10 equivalentsbased on substrate or any specific amount within this range. Thehalogenating catalyst could be 1-20 mol %, 5-15 mol %, or any specificamount within these ranges. The phase transfer catalyst could be 1-20mol %, 5-15 mol %, or any specific amount within these ranges.

A carbon containing compound may include an sp3 C—H bond, and is alsoreferred to as a substrate or target herein. Examples of carboncontaining compounds include but are not limited to simple alkanes;neopentane; toluene; cyclohexane; norcarne; simple hydrocarbons;trans-decalin; 5α-cholestane; sclarolide; 1, 3, 5(10)-estratrien-17-one;(1R,4aS,8aS)-octahydro-5,5,8a-trimethyl-1-(3-oxobutyl)-naphtalenone;(1R,4S,6S,10S)-4,12,12-trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one;levomethorphan; lupine; 20-methyl-5alpha(H)-pregnane; isolongifolanone;caryophyllene acetate; N-acetyl-gabapentin methyl ester;acetyl-amantidine; phthalimido-amantadine; methyloctanoate, and othersaturated fatty acid esters; N-acetyl-Lyrica methyl ester; artemisinin,adapalene; finasteride; N-acetyl-methylphenidate; mecamylamine andN-acetyl-mecamylamine; N-acetyl-memantine; phthalimidi-memantine;N-acetyl-Enanapril precursor methyl ester; progesterone; artemisinin;adapalene; dopamine derivative; pregabalin; cholestane; finasteride;methylphenidate derivative; mecamylamine; gabapentin; memantinederivative; gabapentin; isoleucine derivative; leucine derivative;valine derivative; pregesterone; tramadol; and(1R,4aS,8aS)-5,5,8a-trimethyl-1-(3-oxobutyl)octahydronaphthalen-2(1H)-one.A carbon containing compound may also be any one of the compounds inFIG. 31, 38 or 39. Arrows in FIGS. 38 and 39 indicate positions that maybe halogenated. A carbon containing compound may also include an analogof any carbon containing compound herein. An analog of a carboncontaining compound may include substitution of a moiety in the compoundfor another moiety. The carbon containing compound is a drug or drugcandidate precursor of which non-limiting examples are found in FIGS.31, 38, and 39.

Examples of halogenating agents include but are not limited to ahypohalite, N-chlorosuccinimide (NCS), N-bromosuccinimide, hypochlorousacid, hypobromous acid, hypochlorites, sodium hypochlorite, sodiumhypobromite, calcium hypochlorite, and cyanuric chloride. Thehalogenating agent may be provided by setting conditions to produce ahypohalite in situ.

Examples of halogenating catalysts include but are not limited to metalporphyrins. Metal porphyrins may include manganese, copper, vanadium,chromium, iron, cobalt or nickel. Manganese porphyrin halogenatingcatalysts may include tetraphenylporphyrinatomanganese chloride(hereinafter “Mn(TPP)Cl”), tetramesitylporphyrinatomanganese(hereinafter “Mn(TMP)Cl”) and other similar manganese porphyrins.Manganese porphyrin halogenating catalysts may includetetraphenylporphyrinatomanganese (III) chloride ([Mn^(III)(TPP)Cl]),5,10,15,20-tetramesitylporphyrinatomanganese (III) chloride([Mn^(III)(TMP)Cl]), Mn(III)[tetra-2,6-dichlorophenyl porphyrin, Mn(III)[tetra-2-nitrophenyl porphyrin], Mn(III)[tetra-2-naphthyl porphyrin,Mn(III) [pentachlorophenyl porphyrin, Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octachloroporphyrin],Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octabromoporphyrin], andMn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octanitroporphyrin.

Examples of halogenating catalysts include but are not limited to acatalyst having a metal complexed with a ligand. The ligand may includebut is not limited to a porphyrin, a phthalocyanine, a corrole, anN-pyridylmethyl-tri-aza-cyclononane, an N,N-dipyridylmethylcyclohexadiamine, a tetra-aza-cyclotetra-decane, an N,N-dipyridylmethyl2,2′-dipyrrolidine, an N,N-dipyridylmethyl ethylenediamine, a tripyridylamine (TPA), and a salen. The halogenating catalyst may be atrans-difluoromanganese(IV) porphyrin, Mn^(IV)(TMP)F₂. Halogenatingcatalysts may include a manganese complex in which manganese is in the4+ or 5+ oxidation state and which has at least one fluoride ligandbound to manganese, L5Mn(IV)—F or L₅Mn(V)—F, in which L can be oxygen,nitrogen or halide, such that manganese has octahedral coordination withsix total ligands and a neutral overall charge. Halogenating catalystsmay include a manganese complex in which manganese is in the 4+oxidation state and which has one or two fluoride ligands bound tomanganese, L₅Mn(IV)—F or L₄Mn(IV)—F₂, in which L can be oxygen, nitrogenor halide, such that manganese has octahedral coordination with sixtotal ligands and a neutral overall charge.

Examples of phase transfer catalysts include but are not limited totetrabutylammonium chloride, tetraalkyl ammonium, mixed alkyl ammonium,aryl ammonium, benzyl-trimethylammonium chloride, benzalkonium chloride,benzyl tributylammonium chloride, benzyl triethylammonium chloride,tetrabutyl phosphonium chloride, tetramethyl phosphonium chloride, anddimethyldiphenyl phosphonium chloride.

An embodiment includes a composition including at least one of a carboncontaining compound with an sp3 C—H bond, a halogenating agent, ahalogenating catalyst or a phase transfer catalyst. An embodimentincludes a composition including a partial mix of reactants. The partialmix includes at least one of one of a carbon containing compound with ansp3 C—H bond, a halogenating agent, a halogenating catalyst, or a phasetransfer catalyst ready for mixing with the remaining necessary reactioncomponents. The partial mix may be provided in a method of halogenatinga carbon containing compound with an sp3 C—H bond, where the remainingcomponents of the reaction are combined with at least a portion of thepartial mix. An embodiment includes a kit. The kit may include one ormore containers or wells. A container may include at least one of thecarbon containing compound with an sp3 C—H bond, a halogenating agent, ahalogenating catalyst, or a phase transfer catalyst, but would onlyinclude a subset of the reactants such that the halogenating reactiondoes not proceed until all of the reactants are mixed. A container orwell may include a solvent. The kit may include instructions for mixingall of the necessary reactants from the one or more container and, ifneeded, any other source in order to make a halogenation reactionproceed. All of the necessary reactants may include the carboncontaining compound, the halogenating agent, the halogenating catalyst,and the phase transfer catalyst.

An embodiment provides a method of manganese porphyrin catalyzedhalogenation. The method may include hypohalites as a halogen source.The method may include halogenating a carbon containing compound in thepresence of catalytic amount of Mn(TPP)Cl and tetrabutylammoniumchloride as phase transfer catalyst. A catalytic amount of Mn(TPP)Cl maybe 1-20 mol %, 5-15 mol %, or any specific amount in these ranges. Forexample, reaction of sodium hypochlorite with cyclohexane in a biphasicsystem with Mn(TPP)Cl results in cyclohexyl chloride as the majorproduct at room temperature. Only trace amounts of cyclohexanol,cyclohexanone and other chlorinated products were detected under optimalconditions. The method may be utilized to add any halogen, preferablyCl, Br, I or At. Other halogenating catalysts may replace the Mn(TPP)Cl.In an embodiment, any halogenating catalyst contained herein may be usedin place of the manganese porphyrin.

An embodiment provides a manganese porphyrin mediated aliphatic C—H bondchlorination using sodium hypochlorite as the chlorine source. In thepresence of catalytic amounts of phase transfer catalyst and manganeseporphyrin Mn(TPP)Cl, reaction of sodium hypochlorite with differentunactivated alkanes afforded alkyl chlorides as the major products withonly trace amounts of oxygenation products. A catalytic amount of phasetransfer catalyst may be 1-20 mol %, 5-15 mol %, or any specific amountin these ranges. A catalytic amount of Mn(TPP)Cl may be 1-20 mol %, 5-15mol %, or any specific amount in these ranges. Substrates with strongC—H bonds, for example (but not limited to) neopentane (BDE=˜100kcal/mol) can be also chlorinated with moderate yield. Chlorination of adiagnostic substrate, for example (but not limited to) norcarane,affords rearranged products indicating a long-lived carbon radicalintermediate. Moreover, regioselective chlorination is provided by usinga hindered catalyst, Mn(TMP)Cl. In an embodiment, chlorination oftrans-decalin with Mn(TMP)Cl provided is provided. 95% selectivity formethylene-chlorinated products as well as a preference for the C2position may be obtained in the chlorination of trans-decalin withMn(TMP)Cl. Embodiments also include implementation of the novelhalogenation system applied to complex substrates. With 5α-cholestane asthe substrate, a method of chlorination is provided where only the C2and C3 positions are chlorinated. Using this method, chlorination of5α-cholestane at the C2 and C3 positions may be obtained at a 55% yield.The C2 and C3 positions correspond to the least sterically hinderedmethylene positions in the A-ring. Chlorination of sclareolide at theequatorial C2 chloride is provided. The reaction with 5α-cholestane isillustrative, and other carbon containing compounds may be similarlyhalogenated. In an embodiment, any halogenating catalyst containedherein may be used in place of the manganese porphyrin.

In an embodiment, a method is provided to prepare a cross-couplingreagent. The method includes halogenating a carbon containing compoundas described herein with a Cl or Br. A method is provided to fluorinatea compound by first modifying the compound with a Cl or Br by a methodof halogenating herein, and then replacing the Cl or Br with F. The Clor Br may be replaced with F by nucleophilic substitution. Nucleophilicconditions may include a source of fluoride ion in a suitable solvent.The source of fluoride ion may include but is not limited to silverfluoride, potassium-crown fluoride, tetraalkyl ammonium fluoride ortrialkylamine trihydrofluoride. A suitable solvent may be but is notlimited to acetonitrile.

An embodiment provides drug diversification via selectivemetal-catalyzed halogenation of carbon containing compounds that aredrugs. Drug diversification may include fluorination of the carboncontaining drug. Drug diversification may include halogenating a drugwith a halogenating agent in the presence of a halogenating catalyst anda phase transfer catalyst. Halogenating with Cl or Br may be followed bynucleophilic substitution with F. The method may be utilized forlate-stage drug candidate diversification. The halogenating catalyst maybe a manganese porphyrin.

The development of metalloporphyrin-catalyzed halogenations ofunactivated hydrocarbons could provide a significant new avenue forlate-stage drug candidate diversification. Drug diversification mayinclude direct oxidative C—H fluorination of a drug. Further, therealization of such a process could provide insight into the mechanismsof halogenating enzymes such as chloroperoxidase, a heme-containingchlorinating enzyme, and Syr3, a nonheme Fe(II) R-ketoglutaratedependenthalogenase.

Methods of manganese-catalyzed direct oxidative C—H fluorination usingfluoride ion are embodiments herein. A method of direct oxidativefluorination of a carbon containing compound with an sp3 C—H bondincludes reacting a carbon containing compound with a fluorinating agentin the presence of a fluorinating catalyst and an oxidant.

A carbon containing compound may have a sp3 C—H bond, and is alsoreferred to as a substrate or target herein. Examples of carboncontaining compounds that can be the target of direct oxidative C—Hfluorination include but are not limited to those listed above withrespect to halogenation, cyclic alkanes, steroids, steroid derivatives,5α-androstan-17-one, bornyl acetate, azo-bis-α-phenylethane, trepanoids,simple hydrocarbons, substituted alkanes, ester, tertiary alcohol,ketone and amine substituents, mono-substituted five and seven memberedcycloalkanes, cyclohexane, ethylbenzene, methyl cyclopentanone, methylcyclohexylcarboxylate, methyl cyclohexanol, cycloheylacetate,N-acetyl-gabapentin methyl ester; acetyl-amantidine;phthalimido-amantadine; methyloctanoate, and other saturated fatty acidesters; N-acetyl-Lyrica methyl ester; artemisinin, adapalene;finasteride; N-acetyl-methylphenidate; mecamylamine andN-acetyl-mecamylamine; N-acetyl-memantine; phthalimidi-memantine;N-acetyl-Enanapril precursor methyl ester; progesterone; artemisinin;adapalene; dopamine derivative; pregabalin; cholestane; finasteride;methylphenidate derivative; mecamylamine; gabapentin; memantinederivative; gabapentin; isoleucine derivative; leucine derivative;valine derivative; pregesterone; tramadol; and(1R,4aS,8aS)-5,5,8a-trimethyl-1-(3-oxobutyl)octahydronaphthalen-2(1H)-one.Carbon containing compounds utilized in direct fluorination may furtherinclude any compound illustrated in FIGS. 31, 38 and 39. Arrows in FIGS.38 and 39 indicate positions that may be fluorinated. Similarfluorinations may occur to the targets in FIG. 31. A carbon containingcompound may also include an analog of any carbon containing compoundherein. An analog of a carbon containing compound may includesubstitution of a moiety in the compound for another moiety. The carboncontaining compound is a drug or drug candidate precursor of whichnon-limiting examples are found in FIGS. 31, 38, and 39.

Examples of fluorinating agents include but are not limited to silver(I) fluoride, silver (II) fluoride, tetrabutyl ammonium fluoride(“TBAF”), sodium fluoride, potassium fluoride, tetra alkyl ammoniumfluoride, trialkyl amine trihydrofluoride designated as R₃N(HF)₃ or asthe ammonium salt [R₃NH][H₂F₃], and potassium crown ether fluoride.

Examples of fluorinating catalysts include but are not limited to acatalyst having a metal complexed with a ligand. The ligand may includebut is not limited to a porphyrin, a phthalocyanine, a corrole, anN-pyridylmethyl-tri-aza-cyclononane, an N,N-dipyridylmethylcyclohexadiamine, a tetra-aza-cyclotetra-decane, an N,N-dipyridylmethyl2,2′-dipyrrolidine, an N,N-dipyridylmethyl ethylenediamine, a tripyridylamine (TPA), and a salen. The metal may be V, Mn, Fe, Co and Ni.Fluorinating catalysts may include manganese porphyrins includingMn(TPP)Cl, Mn(TMP)Cl, Mn^(III)(TPP)C, Mn^(III)(TMP)Cl or other similarmanganese porphyrins. The fluorinating catalyst may be atrans-difluoromanganese(IV) porphyrin, Mn^(IV)(TMP)F₂. Fluorinatingcatalysts may include a manganese complex in which manganese is in the4+ or 5+ oxidation state and which has at least one fluoride ligandbound to manganese, L5Mn(IV)—F or L₅Mn(V)—F, in which L can be oxygen,nitrogen or halide, such that manganese has octahedral coordination withsix total ligands and a neutral overall charge. Fluorinating catalystsmay include a manganese complex in which manganese is in the 4+oxidation state and which has one or two fluoride ligands bound tomanganese, L₅Mn(IV)—F or L₄Mn(IV)—F₂, in which L can be oxygen, nitrogenor halide, such that manganese has octahedral coordination with sixtotal ligands and a neutral overall charge.

Oxidants may be meta-chloroperoxybenzoic acid (mCPBA), idosylbenzene,peroxyacid, alkyl peroxide, peroxy sulfate(oxone), peroxycarbonate,peroxyborate, iodosyl mesitylene, pentafluoro-iodosylbenzene, benzenedifluoroiodinane [phenyl-IF2], diacetoxyiodobenzene, 2-iodosylbenzoicacid, peroxyacetic acid, peroxyphthalic acid, and peroxytungstic acid.

An embodiment includes a composition including at least one of a carboncontaining compound with an sp3 C—H bond, a fluorinating agent, afluorinating catalyst, or an oxidant. An embodiment includes acomposition including a partial mix of reactants. The partial mixincludes at least one of one of a carbon containing compound with an sp3C—H bond, a fluorinating agent, a fluorinating catalyst, or an oxidantready for mixing with the remaining necessary reaction components. Thepartial mix may be provided in a method of fluorinating a carboncontaining compound, where the remaining components of the reaction arecombined with at least a portion of the partial mix. An embodimentincludes a kit. The kit may include one or more container. Eachcontainer would include at least one of a carbon containing compound, afluorinating agent, a fluorinating catalyst, or an oxidant, but wouldonly include a subset of the reactants such that the fluorinatingreaction does not proceed until all of the reactants are added. The kitmay include instructions for mixing all of the necessary reactants fromthe one or more container and, if needed, any other source in order tomake the reaction proceed. All of the necessary reactants may includethe carbon containing compound, the fluorinating agent, the fluorinatingcatalyst, and the oxidant.

An embodiment includes a composition comprising a manganese complex inwhich manganese is in the 4+ or 5+ oxidation state and which has atleast one fluoride ligand bound to manganese, L5Mn(IV)—F or L₅Mn(V)—F,in which L can be oxygen, nitrogen or halide, such that manganese hasoctahedral coordination with six total ligands and a neutral overallcharge. An embodiment includes a composition comprising a manganesecomplex in which manganese is in the 4+ oxidation state and which hasone or two fluoride ligands bound to manganese, L₅Mn(IV)—F orL4Mn(IV)—F₂, in which L can be oxygen, nitrogen or halide, such thatmanganese has octahedral coordination with six total ligands and aneutral overall charge.

The manganese porphyrin-fluoride ion direct oxidative fluorinationherein accomplishes this transformation under mild conditions. Simplealkanes, terpenoids and even steroids can be selectively fluorinated atotherwise inaccessible sites in 50-80% yield. As an example, decalin wasfluorinated predominantly at the C2 and C3 methylene positions. Also,bornyl acetate afforded exo-5-fluoro-bornyl acetate and5α-androstan-17-one was fluorinated selectively in the A ring.Mechanistic analysis indicates that the regioselectivity for C—H bondcleavage is directed by an oxomanganese(V) catalyst intermediate, whilefluorine delivery is suggested to occur via an unusual manganese(IV)fluoride that has been isolated and structurally characterized. Thisone-step C—H fluorination using fluoride ion is rapid enough to beapplied to 18F radiofluorination for positron emission applications.

Embodiments herein place fluorine at such inaccessible sites inbiomolecules and drug candidates. Fluorination of drugs can block sitesof phase I metabolism by cytochrome P450 enzymes as well as improvingtarget binding affinities. Further, the incorporation of ¹⁸F intobiomolecules can allow direct imaging of metabolic activity and drugtargets using the exquisite sensitivity of positron emission tomography.An embodiment includes any carbon containing compound halogenated orfluorinated by a method herein. The products include modified drugs andimaging agents.

An embodiment includes a method of creating fluorinated analogs of drugmolecules, natural products and precursors thereof in which sp³ C—Hbonds are replaced with fluorine using fluoride ion as a fluorinesource.

An embodiment includes a method of incorporating ¹⁸F from fluoride ioninto known drug molecules, natural products and precursors thereof inwhich sp³ C—H bonds are replaced with fluorine.

Direct oxidative fluorination herein is similar to the halogenationreactions described in examples 1-6, but with several changes in thereaction conditions and reaction reagents to lead to fluorination. Themethod may include manganese porphyrin catalyzed halogenation where thehalide is fluoride. The method may include at least one of silver(I)fluoride or silver(II) fluoride as a halogen source. The method mayinclude halogenating a carbon containing compound in the presence ofcatalytic amount of Mn(TPP)Cl and tetrabutylammonium fluoride, which canbe an additional source of fluoride or may act as a phase transfercatalyst (PTC). The method may employ both silver(I) fluoride andtetrabutylammonium fluoride and fluorine sources. The method may alsoemploy silver(I) (18-F)fluoride, silver(II) (18-F)fluoride andtetrabutylammonium (18-F)fluoride as sources and the 18-F labeledproducts may be used for positron emitting tomography (PET)applications. An oxidant may be used. The oxidant may be one such as aperoxyacid, alkyl peroxide, peroxy sulfate (Oxone®), peroxycarbonate orperoxyborate. For example, reaction of m-chloroperoxybenzoic acid withcyclooctane in a monophasic system employing either acetonitrile ormethylene chloride as solvents, or both by direct oxidative fluorinationresults in cyclooctyl fluoride in greater than 50% conversion.Temperatures between and including 0° C. and 80° C. may be used. Thetemperature may be in a range between any two integer value temperaturesselected from 0° C. to 80° C. The temperature may be in a range betweenand including 0° C. and 10° C., 10° C. and 20° C., 20° C. and 30° C.,30° C. and 40° C., 40° C. and 50° C., 50° C. and 60° C., 60° C. and 70°C., or 70° C. and 80° C. The temperature may be any one integer valuetemperature selected from those including and between 0° C. and 80° C.Temperatures between room temperature and 70° C. may be used. Thetemperature may be any one temperature including and between roomtemperature and 70° C. Temperatures between 25° C. and 70° C. may beused. The temperature may be any temperature including and between 25°C. and 70° C. Only trace amounts of cyclooctanol, cyclooctanone or otherfluorinated or chlorinated products were detected under optimalconditions, as discussed in example 7, general procedures. Thetemperature ranges in this paragraph may also be provided in a method ofhalogenating herein.

An embodiment includes a composition comprisingtrans-difluoromanganese(IV) porphyrin, Mn^(IV)(TMP)F₂. The structure ofMn^(IV)(TMP)F₂ is illustrated in FIGS. 2, 8 and 27.

An embodiment includes a method of fluorinating a compound with 18-F (or¹⁸F), and the compounds produced thereby. Fluorinating a carboncontaining compound with 18-F may be achieved by a method ofhalogenation followed by nucleophilic substitution. Fluorinating acarbon containing compound with 18-F may be achieved by a method ofdirect oxidative C—H fluorination herein. The method may includefluorinating the compound with 18-F on site for delivery to the patientshortly after synthesis. The visualization of cellular processes bymolecular imaging is a promising and non-invasive way to observe diseasestates and to improve the diagnoses (See Signore, A., Mather, S. J.,Piaggio, G., Malviya, G., and Dierckx, R. A. Molecular imaging ofinflammation/infection: nuclear medicine and optical imaging agents andmethods. Chem. Rev. 2010, 110, 3112-3145; and Pysz, M. A., Gambhir, S.S., and Willmann, J. K. Molecular imaging: current status and emergingstrategies. Clin. Radiol. 2010, 65, 500-516, which are incorporatedherein by reference as if fully set forth). Positron-emission tomography(PET) in particular, has emerged as a modality of choice because ityields well-resolved images with excellent sensitivity (See Wong, F. C.,and Kim, E. E. A review of molecular imaging studies reaching theclinical stage. Eur. J. Radiol. 2009, 70, 205-211; Ametamey, S. M.,Honer, M., and Schubiger, P. A. Molecular imaging with PET. Chem. Rev.2008, 108, 1501-1516; and Chen, K., and Conti, P. S. Target-specificdelivery of peptide-based probes for PET imaging. Adv. Drug DeliveryRev. 2010, 62, 1005-1022, which are incorporated herein by reference asif fully set forth). Among the seven positron-emitting isotopes, ¹⁸F hasthe advantages of a two-hour half and a β+-emission at 635 keV (SeeMiller, P. W., Long, N. J., Vilar, R., and Gee, A. D. Synthesis of ¹¹C,¹⁸F, ¹⁵O, and ¹³N radiolabels for positron emission tomography. Angew.Chem., Int. Ed. 2008, 47, 8998-9033; and Cai, L., Lu, S., and Pike, V.W. Chemistry with [¹⁸F] fluoride ion. Eur. J. Org. Chem. 2008,2853-2873, which is incorporated herein by reference as if fully setforth). Imaging agents such as ¹⁸F-fluorodeoxyglucose (18F-FDG) haveproved to be efficacious for imaging tissue and cells with high glucosemetabolism (See Wadsak, W., and Mitterhauser, M. Basic principles ofradiopharmaceuticals for PET/CT. Eur. J. Radiol. 2010, 73, 461-469,which is incorporated herein by reference as if fully set forth). Ashort-coming of current methods of ¹⁸F labeling is that the usualreplacement of an oxygen functional group with fluorine changes thepolarity of the detection molecule. The method of direct oxidativefluorination herein allows for the one-step replacement of acarbon-bound hydrogen, which has the advantages of using ¹⁸F from afluoride ion source and creating a detection molecule that does notchange the hydrogen bonding pattern of the starting compound.

An embodiment includes visualization by steps including 1) directoxidative C—H fluorination of a carbon containing compound by a methodherein to create an imaging agent, 2) administration of the imagingagent to a patient, and 3) positron emission tomography of the patient.An embodiment includes visualization by steps including 1) Cl or Brhalogenation of a carbon containing compound with an sp3 C—H by a methodherein, followed by nucleophilic substitution with F to create animaging agent, 2) administration of the imaging agent to a patient, and3) positron emission tomography of the patient.

An embodiment includes a composition including a partial mix ofreactants necessary to create an imaging agent. The partial mix includesat least one of one of a carbon containing compound, a fluorinatingagent, a fluorinating catalyst, or an oxidant ready for mixing with theremaining necessary reaction components. The fluorinating agent mayinclude an ¹⁸F source. The partial mix may be provided in a method offluorinating a carbon containing compound with ¹⁸F, where the remainingcomponents of the reaction are combined with at least a portion of thepartial mix. An embodiment includes a kit for the creation of an imagingagent. The kit may include one or more container. Each container wouldinclude at least one of a carbon containing compound, a fluorinatingagent, a fluorinating catalyst, or an oxidant, but would only include asubset of the reactants such that the fluorinating reaction does notproceed until all of the reactants are added. The kit may includeinstructions for mixing all of the necessary reactants from the one ormore container and, if needed, any other source in order to make thereaction proceed. All of the necessary reactants may include the carboncontaining compound, the fluorinating agent, the fluorinating catalyst,and the oxidant. The fluorinating agent may include an ¹⁸F source.

An embodiment provides a manganese porphyrin mediated aliphatic C—H bondfluorination using tetrabutylammonium fluoride/silver(I) fluoride as thefluorine source. In the presence of catalytic amounts of manganeseporphyrin Mn(TPP)Cl, or similar manganese porphyrins or phthalocyaninesor porphyrazines, reaction of mCPBA or Oxone with different unactivatedalkanes afforded alkyl fluorides as the major products with only traceamounts of oxygenation or chlorinated products. Substrates with strongC—H bonds, for example (but not limited to) neopentane (BDE=˜100kcal/mol) can be also fluorinated with moderate yield. Moreover,regioselective fluorination is provided by using a hindered catalyst.The hindered catalyst may be Mn(TMP)Cl. In an example, fluorination oftrans-decalin with Mn(TMP)Cl provided 85% selectivity formethylene-fluorinated products. A preference for the C2 position may beobtained in the fluorination of trans-decalin with Mn(TMP)Cl.Embodiments also include implementation of the novel method of directoxidative fluorination system applied to complex substrates. The complexsubstrate may be but is not limited to 5α-cholestane, and the method ofdirect oxidative fluorination results in fluorination of positions inring A of 5α-cholestane. Embodiments also include direct oxidativefluorination of sclareolide at the equatorial C2 position andfluorination of bornyl acetate at the C3 position under theseconditions.

The combination of tetrabutylammonium fluoride, silver fluoride andvarious oxidants described above were observed to transform the startingmanganese(III) chloride catalyst into the active fluorinating catalyst.These active forms of the catalyst include manganese(III) monofluorideas the axial metal ligand, a trans-difluoromanganese(III), atrans-oxo-fluoromanganese(IV) and trans-difluoromanganese(IV) and atrans-oxofluoromanganese(V). Manganese may be substituted with otherfirst row transition metals including but not limited to copper,vanadium, chromium, iron, cobalt and nickel. An embodiment includes acomposition including any of the catalysts above. An embodiment includesa composition including at least one of the catalysts above, afluorinating agent, an oxidant or a carbon containing compound.

In some embodiments above, specific halogenating agents that arehypohalites are utilized. In situ production of hypohalite using saidmanganese porphyrins, a halide and a peroxide may also be provided inembodiments herein. See Lahaye, D. and Groves, J. T. J. Inorg. Biochem.2007, 101, 1786-1797; and N. Jin, J. L. Bourassa, S. C. Tizio, and J. T.Groves, “Rapid, Reversible Oxygen Atom Transfer between anOxomanganese(V) Porphyrin and Bromide. A Haloperoxidase Mimic withEnzymatic Rates.” Angew. Chem. 2000, 39, 3849-3851, which areincorporated herein by reference as if fully set forth. In anembodiment, conditions may be provided that produce hypohalites in situin place or in addition to directly utilizing a hypohalite. For example,a halogenating method may include providing peroxide, a halide and amanganese porphyrin along with the carbon containing compound. Ahalogenating method may include providing peroxide, a halide and anickel porphyrin along with the carbon containing compound.

Embodiments include a compound comprising fluoro-buspirone and a methodof synthesis thereof. Referring to FIG. 7A, a fluoro-buspirone compoundis illustrated. Example 26, below, outlines the synthesis offluoro-buspirone.

In an embodiment, shorter reaction times for 18F applications may bepresent. For example, much shorter reaction times (about 1 hr) could beachieved by adding iodosylbenzene oxidant while maintaining the reactionmixture between 60 and 80° C. Also, by using mCPBA as the oxidant, up to40% yields could be obtained within 1 hr at room temperature and up to60° C. Each addition of 1 equiv. oxidant may be followed by anothercharge of Mn(TMP)Cl catalyst (13.2 mg, 1 mmol %) added dissolved inminimal amount of solvents.

An embodiment includes a composition comprising at least one halogenatedcompound described herein, or an analog thereof. An embodiment includesa composition comprising at least one fluorinated compound describedherein, or an analog thereof. An embodiment includes a compositioncomprising an organic compound with a halogen in place of an aliphatichydrogen. The halogen replacing an aliphatic hydrogen is not limited tobut may be Cl, Br, or F. An embodiment includes a composition comprisingan organic compound with an F in place of an aliphatic hydrogen.

An embodiment includes a composition comprising the product of a methodof halogenating a carbon containing compound having an sp3 C—H bondherein. The product may be from the method as it is conducted on anytarget herein or an analog thereof.

An embodiment includes a composition comprising the product of a methodof halogenating a carbon containing compound having an sp3 C—H bondherein with Cl or Br to obtain a halogenated product, followed bynucleophilic substitution of the halogenated product with F. The productmay be from the method as it is conducted on any target herein or ananalog thereof.

An embodiment includes a composition comprising the product of a methodof fluorinating a carbon containing compound having an sp3 C—H bondherein. The product may from the method as it is conducted on any targetcontained herein or an analog thereof.

The fluorinated drug molecules created by methods herein will havenearly the same steric size as the parent drug. But they will containonly one, or possibly two or three fluorine atoms. Fluorine NMRspectroscopy is a very powerful tool for studying such molecules since19F is NMR active and 100% abundant. Further fluorine has nearly as higha detection level as protons and, importantly, a much larger chemicalshift range. Moreover, when a fluorinated molecule binds to anothermolecule, such as a protein receptor, the fluorine chemical shift canchange by as much as 8 ppm, while proton chemical shift changes of onlya few tenths (+/−0.3) of a ppm are observed in similar situations. Thecovalent structure of the molecule is not changed upon binding, butmolecular electric fields are affected by such things as hydrogenbonding and hydrogen bonding does occur to fluorine. Accordingly,fluorinated derivatives of drug molecules have the utility of beingdetectable by fluorine NMR that will not be complicated by the largenumber of protons found in such molecules. Further, fluorine NMRchemical shift changes will indicate the degree of binding of thefluorinated molecule to a receptor binding site.

EMBODIMENTS

The following list includes particular embodiments of the presentinvention. The list, however, is not limiting and does not excludealternate embodiments, as would be appreciated by one of ordinary skillin the art.

1. A method of direct oxidative C—H fluorination of a carbon containingcompound having an sp3 C—H bond comprising: combining a carboncontaining compound, a fluorinating agent, a fluorinating catalyst, andan oxidant.

2. The method of embodiment 1, wherein the carbon containing compound isadded in a concentration from 1 mM to 5 M, the fluorinating agent isadded in a concentration from 1 mM to 5 M, the fluorinating catalyst isadded in a concentration from 1 mol % to 20 mol %, and the oxidant isadded in a concentration from 1 mM to 1 M in each addition.

3. The method of any one or more of the preceding embodiments furthercomprising allowing the combined carbon containing compound,fluorinating agent, fluorinating catalyst, and oxidant to react for 30minutes to 12 hours.

4. The method of any one or more of the preceding embodiments furthercomprising maintaining the carbon containing compound, the fluorinatingagent, the fluorinating catalyst, and the oxidant at a temperature from−20° C. to +100° C.

5. The method of any one or more of the preceding embodiments, whereincombining further comprises: mixing the fluorinating catalyst, thefluorinating agent, and the carbon containing compound in a solvent toform a first mixture; providing an inert gas over the first mixture; andadding the oxidant to the first mixture to form a second mixture.

6. The method of any one or more of the preceding embodiments, whereinthe carbon containing compound includes a compound selected from thegroup consisting of neopentane; toluene; cyclohexane; norcarane;trans-decalin; 5α-cholestane; sclareolide; 1, 3,5(10)-estratrien-17-one;(1R,4aS,8aS)-octahydro-5,5,8a-trimethyl-1-(3-oxobutyl)-naphtalenone;(1R,4S,6S,10S)-4,12,12-trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one;levomethorphan; lupine; 20-methyl-5alpha(H)-pregnane; isolongifolanone;caryophyllene acetate; N-acetyl-gabapentin methyl ester;acetyl-amantidine; phthalimido-amantadine; methyloctanoate; saturatedfatty acid esters; N-acetyl-Lyrica methyl ester; artemisinin, adapalene;finasteride; N-acetyl-methylphenidate; mecamylamine;N-acetyl-mecamylamine; N-acetyl-memantine; phthalimidi-memantine;N-acetyl-enanapril precursor methyl ester; progesterone; artemisinin;adapalene; dopamine derivative; pregabalin; cholestane; finasteride;methylphenidate derivative; mecamylamine; gabapentin; memantinederivative; gabapentin; rimantadine derivative; isoleucine derivative;leucine derivative; valine derivative; pregesterone; tramadol; enalaprilprecursor;(1R,4aS,8aS)-5,5,8a-trimethyl-1-(3-oxobutyl)octahydronaphthalen-2(1H)-one;phenylalanine; donepezil precursor; amphetamine; 6-tocopherol form ofvitamin E; tyrosine; melatonin; tryptophan; estrone acetate;progesterone; dopamine; homophenylalanine; DOPA; ibuprofen methyl ester;buspirone; eticyclidine; memantine; amantadine; lyrica; lubiprostone;penridopril; fosinopril; N-Phth amantadine; N-Phth Memantine;2-adamantanone; rimantadine analogue; adapalene precursor; perindoprilprecursor; protected gabapentin; methyl octanoate; methyl nonanate;methyl hexanoate; cyclohexyl acetate; and cyclohexane carboxylic acidmethyl ester; or an analog of any of the foregoing.

7. The method of any one or more of the preceding embodiments, whereinthe carbon containing compound is a drug or drug candidate precursor.

8. The method of any one or more of the preceding embodiments, whereinthe fluorinating agent is selected from the group consisting of silver(I) fluoride, silver (II) fluoride, tetrabutyl ammonium fluoride, sodiumfluoride, potassium fluoride, silver fluoride and tetra alkyl ammoniumfluoride, trialkyl amine trihydrofluoride R₃N(HF)₃, the ammonium salt[R₃NH][H₂F₃], and potassium crown ether fluoride.

9. The method of any one or more of the preceding embodiments, whereinthe fluorinating catalyst includes a metal complexed with a ligandselected from the group consisting of a porphyrin, a phthalocyanine, acorrole, an N-pyridylmethyl-tri-aza-cyclononane, an N,N-dipyridylmethylcyclohexadiamine, a tetra-aza-cyclotetra-decane, an N,N-dipyridylmethyl2,2′-dipyrrolidine, an N,N-dipyridylmethyl ethylenediamine, a tripyridylamine (TPA), a salen, a salophen, a phthalocyanine, and a porphyrazine.

10. The method of embodiment 5, wherein the metal is selected from thegroup consisting of manganese, copper, vanadium, chromium, iron, cobaltand nickel.

11. The method of any one or more of the preceding embodiments, whereinthe fluorinating catalyst is a manganese porphyrin.

12. The method of embodiment 11, wherein the manganese porphyrin isselected from the group consisting of Mn(TPP)Cl, Mn(TMP)Cl,Mn^(III)(TPP)C, Mn^(III)(TMP)Cl, Mn^(IV)(TMP)F₂,Mn(III)[tetra-2,6-dichlorophenyl porphyrin, Mn(III) [tetra-2-nitrophenylporphyrin], Mn(III)[tetra-2-naphthyl porphyrin, Mn(III)[pentachlorophenyl porphyrin,Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octachloroporphyrin], Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octabromoporphyrin], andMn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octanitroporphyrin

13. The method of any one or more of the preceding embodiments, whereinthe fluorinating catalyst is a manganese complex having at least onefluoride ligand bound to the manganese and the formula L₅Mn(IV)—F, whereL is selected from the group including oxygen, nitrogen, and halide, andthe manganese has octahedral coordination with six total ligands and aneutral overall charge.

14. The method of any one or more of the preceding embodiments, whereinthe fluorinating catalyst is a manganese complex having at least onefluoride ligand bound to the manganese and the formula L₅Mn(V)—F, whereL is selected from the group consisting of oxygen, nitrogen and halide,and the manganese has octahedral coordination with six total ligands anda neutral overall charge.

15. The method of any one or more of the preceding embodiments, whereinthe fluorinating catalyst is a manganese complex having one or twofluoride ligands bound to the manganese and the formula L₅Mn(IV)—F orL₄Mn(IV)—F₂, where L is selected from the group consisting of oxygen,nitrogen and halide, and the manganese has octahedral coordination withsix total ligands and a neutral overall charge.

16. The method of any one or more of the preceding embodiments, whereinthe oxidant is selected from the group consisting ofmeta-chloroperoxybenzoic acid (mCPBA), idosylbenzene, peroxyacid, alkylperoxide, peroxy sulfate(oxone), peroxycarbonate, peroxyborate, iodosylmesitylene, pentafluoro-iodosylbenzene, benzene difluoroiodinane[phenyl-IF2], diacetoxyiodobenzene, 2-iodosylbenzoic acid, peroxyaceticacid, peroxyphthalic acid, and peroxytungstic acid.

17. The method of any one or more of the preceding embodiments, whereinthe fluorinating agent includes ¹⁸F and a product produced by the methodincludes ¹⁸F.

18. A composition comprising the product of the method of any one ofembodiments 1-17.

19. A composition comprising the product of embodiment 17.

20. A method of visualization comprising: fluorinating a carboncontaining compound having an sp3 C—H bond by the method of any one ofembodiments 1-17, where the fluorinating agent includes ¹⁸F and aproduct produced by the method includes ¹⁸F to create an imaging agent;administering the imaging agent to a patient; and performing positronemission tomography on the patient.

21. A composition comprising at least two or more of a carbon containingcompound, a fluorinating agent, a fluorinating catalyst and an oxidant.

22. A composition comprising a trans-difluoromanganese(IV) porphyrinMn^(IV)(TMP)F₂.

23. A composition comprising a manganese complex having at least onefluoride ligand bound to the manganese and the formula L₅Mn(IV)—F, whereL is selected from the group including oxygen, nitrogen, and halide, andthe manganese has octahedral coordination with six total ligands and aneutral overall charge.

24. A composition comprising a manganese complex having at least onefluoride ligand bound to the manganese and the formula L₅Mn(V)—F, whereL is selected from the group consisting of oxygen, nitrogen and halide,and the manganese has octahedral coordination with six total ligands anda neutral overall charge.

25. A composition comprising a manganese complex having one or twofluoride ligands bound to the manganese and the formula L₅Mn(IV)—F orL₄Mn(IV)—F₂, where L is selected from the group consisting of oxygen,nitrogen and halide, and the manganese has octahedral coordination withsix total ligands and a neutral overall charge.

26. A composition comprising a fluoro-buspirone.

27. A composition comprising at least two or more of a carbon containingcompound having an sp3 C—H bond, a fluorinating agent, a fluorinatingcatalyst, or an oxidant.

28. The composition of embodiment 27, wherein the carbon containingcompound includes a compound selected from the group consisting ofneopentane; toluene; cyclohexane; norcarane; trans-decalin;5α-cholestane; sclareolide; 1, 3, 5(10)-estratrien-17-one;(1R,4aS,8aS)-octahydro-5,5,8a-trimethyl-1-(3-oxobutyl)-naphtalenone;(1R,4S,6S,10S)-4,12,12-trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one;levomethorphan; lupine; 20-methyl-5alpha(H)-pregnane; isolongifolanone;caryophyllene acetate; N-acetyl-gabapentin methyl ester;acetyl-amantidine; phthalimido-amantadine; methyloctanoate; saturatedfatty acid esters; N-acetyl-Lyrica methyl ester; artemisinin, adapalene;finasteride; N-acetyl-methylphenidate; mecamylamine;N-acetyl-mecamylamine; N-acetyl-memantine; phthalimidi-memantine;N-acetyl-enanapril precursor methyl ester; progesterone; artemisinin;adapalene; dopamine derivative; pregabalin; cholestane; finasteride;methylphenidate derivative; mecamylamine; gabapentin; memantinederivative; gabapentin; rimantadine derivative; isoleucine derivative;leucine derivative; valine derivative; pregesterone; tramadol; enalaprilprecursor;(1R,4aS,8aS)-5,5,8a-trimethyl-1-(3-oxobutyl)octahydronaphthalen-2(1H)-one; phenylalanine; donepezil precursor; amphetamine; 6-tocopherolform of vitamin E; tyrosine; melatonin; tryptophan; estrone acetate;progesterone; dopamine; homophenylalanine; DOPA; ibuprofen methyl ester;buspirone; eticyclidine; memantine; amantadine; lyrica; lubiprostone;penridopril; fosinopril; N-Phth amantadine; N-Phth Memantine;2-adamantanone; rimantadine analogue; adapalene precursor; perindoprilprecursor; protected gabapentin; methyl octanoate; methyl nonanate;methyl hexanoate; cyclohexyl acetate; and cyclohexane carboxylic acidmethyl ester; or an analog of any one of the foregoing.

29. The composition of any one or more of the preceding embodiments,wherein the fluorinating agent is selected from the group consisting ofsilver (I) fluoride, silver (II) fluoride, tetrabutyl ammonium fluoride,sodium fluoride, potassium fluoride, silver fluoride and tetra alkylammonium fluoride, trialkyl amine trihydrofluoride R₃N(HF)₃, theammonium salt [R₃NH][H₂F₃] and potassium crown ether fluoride.

30. The composition of any one or more of the preceding embodiments,wherein the fluorinating catalyst includes a metal complexed with aligand selected from the group consisting of a porphyrin, aphthalocyanine, a corrole, an N-pyridylmethyl-tri-aza-cyclononane, anN,N-dipyridylmethyl cyclohexadiamine, a tetra-aza-cyclotetra-decane, anN,N-dipyridylmethyl 2,2′-dipyrrolidine, an N,N-dipyridylmethylethylenediamine, a tripyridyl amine (TPA), a salen, a salophen, aphthalocyanine, and a porphyrazine.

31. The composition of embodiment 30, wherein the metal is selected fromthe group consisting of manganese, copper, vanadium, chromium, iron,cobalt and nickel.

32. The composition of any one or more of the preceding embodiments,wherein the fluorinating catalyst is a manganese porphyrin.

33. The composition of embodiment 32, wherein the manganese porphyrin isselected from the group consisting of Mn(TPP)Cl, Mn(TMP)Cl,Mn^(III)(TPP)C, Mn^(III)(TMP)Cl, Mn^(IV)(TMP)F₂,Mn(III)[tetra-2,6-dichlorophenyl porphyrin, Mn(III)[tetra-2-nitrophenylporphyrin], Mn(III)[tetra-2-naphthyl porphyrin, Mn(III)[pentachlorophenyl porphyrin,Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octachloroporphyrin], Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octabromoporphyrin], and Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octanitroporphyrin.

34. The composition of any one or more of the preceding embodiments,wherein the fluorinating catalyst is a manganese complex having at leastone fluoride ligand bound to the manganese and the formula L₅Mn(IV)—F,where L is selected from the group consisting of oxygen, nitrogen, andhalide, and the manganese has octahedral coordination with six totalligands and a neutral overall charge.

35. The composition of any one or more of the preceding embodiments,wherein the fluorinating catalyst is a manganese complex having at leastone fluoride ligand bound to the manganese and the formula L₅Mn(V)—F,where L is selected from the group consisting of oxygen, nitrogen andhalide, and the manganese has octahedral coordination with six totalligands and a neutral overall charge.

36. The composition of any one or more of the preceding embodiments,wherein the fluorinating catalyst is a manganese complex having one ortwo fluoride ligands bound to the manganese and the formula L₅Mn(IV)—For L₄Mn(IV)—F₂, where L is selected from the group consisting of oxygen,nitrogen and halide, and the manganese has octahedral coordination withsix total ligands and a neutral overall charge.

37. The composition of any one or more of the preceding embodiments,wherein the oxidant is selected from the group consisting ofmeta-chloroperoxybenzoic acid (mCPBA), idosylbenzene, peroxyacid, alkylperoxide, peroxy sulfate(oxone), peroxycarbonate, peroxyborate, iodosylmesitylene, pentafluoro-iodosylbenzene, benzene difluoroiodinane[phenyl-IF2], diacetoxyiodobenzene, 2-iodosylbenzoic acid, peroxyaceticacid, peroxyphthalic acid, and peroxytungstic acid.

38. The composition of any one or more of the preceding embodiments,wherein the fluorinating agent includes ¹⁸F.

39. A kit comprising one or more container, wherein each containerincludes at least one reactant for a fluorination reaction selected fromthe group consisting of a carbon containing compound, a fluorinatingagent, a fluorinating catalyst, and an oxidant, wherein the compositionincludes at least one fewer substance than required to make afluorination reaction proceed.

40. The kit of embodiment 39, further comprising a container having asolvent.

41. The kit of any one or more of the preceding embodiments, wherein theone or more containers in combination include all the substancesrequired to make the fluorination reaction proceed.

42. The kit of any one or more of the preceding embodiments, furthercomprising instructions for mixing the reactants from the at least onecontainer.

43. A composition comprising a product of a method of direct oxidativeC—H fluorination of a carbon containing compound having an sp3 C—H bondcomprising combining a carbon containing compound, a fluorinating agent,a fluorinating catalyst, and an oxidant.

44. The composition of embodiment 43, wherein the carbon containingcompound is neopentane; toluene; cyclohexane; norcarane; trans-decalin;5α-cholestane; sclareolide; 1, 3, 5(10)-estratrien-17-one;(1R,4aS,8aS)-octahydro-5,5,8a-trimethyl-1-(3-oxobutyl)-naphtalenone;(1R,4S,6S,10S)-4,12,12-trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one;levomethorphan; lupine; 20-methyl-5alpha(H)-pregnane; isolongifolanone;caryophyllene acetate; N-acetyl-gabapentin methyl ester;acetyl-amantidine; phthalimido-amantadine; methyloctanoate; saturatedfatty acid esters; N-acetyl-Lyrica methyl ester; artemisinin, adapalene;finasteride; N-acetyl-methylphenidate; mecamylamine;N-acetyl-mecamylamine; N-acetyl-memantine; phthalimidi-memantine;N-acetyl-enanapril precursor methyl ester; progesterone; artemisinin;adapalene; dopamine derivative; pregabalin; cholestane; finasteride;methylphenidate derivative; mecamylamine; gabapentin; memantinederivative; gabapentin; rimantadine derivative; isoleucine derivative;leucine derivative; valine derivative; pregesterone; tramadol; enalaprilprecursor;(1R,4aS,8aS)-5,5,8a-trimethyl-1-(3-oxobutyl)octahydronaphthalen-2(1H)-one;phenylalanine; donepezil precursor; amphetamine; 6-tocopherol form ofvitamin E; tyrosine; melatonin; tryptophan; estrone acetate;progesterone; dopamine; homophenylalanine; DOPA; ibuprofen methyl ester;buspirone; eticyclidine; memantine; amantadine; lyrica; lubiprostone;penridopril; fosinopril; N-Phth amantadine; N-Phth Memantine;2-adamantanone; rimantadine analogue; adapalene precursor; perindoprilprecursor; protected gabapentin; methyl octanoate; methyl nonanate;methyl hexanoate; cyclohexyl acetate; and cyclohexane carboxylic acidmethyl ester; or an analog of any one of the foregoing.

45. A composition comprising any fluorinating catalyst herein.

46. A composition comprising the product of any reaction herein.

Further embodiments herein may be formed by supplementing an embodimentwith one or more element from any one or more other embodiment herein,and/or substituting one or more element from one embodiment with one ormore element from one or more other embodiment herein.

EXAMPLES

The following non-limiting examples are provided to illustrateparticular embodiments. The embodiments throughout may be supplementedwith one or more detail from one or more example below, and/or one ormore element from an embodiment may be substituted with one or moredetail from one or more example below.

As discussed herein, substrates and targets are carbon containingcompounds that halogenated or fluorinated by the methods herein.

Example 1 Mn(TPP)Cl Catalyzed Halogenation

It was found that a biphasic system with catalytic amounts of Mn(TPP)Cl,tetrabutylammonium chloride as a phase transfer catalyst (PTC), andsodium hypochlorite transformed a variety of simple alkanes to alkylchlorides with high selectivity (Table 1, below). Only trace amounts ofoxygenated and other chlorinated products were detected under optimalconditions. There was negligible reaction in the absence of the Mn orPTC. Interestingly, even substrates with strong C—H bonds, such asneopentane (BDE=˜100 kcal/mol) could be chlorinated with a useful yieldby using Mn(TMP)Cl, as the catalyst. When toluene was used as thesubstrate, the benzylic position was chlorinated exclusively.Interestingly, cyclohexane and toluene were found to have similarreactivities in a competitive reaction, despite the 11 kcal/moldifference in C—H BDE. Moreover, when norcarane was used as a diagnosticsubstrate, the major product was rearranged, indicating the involvementof a long-lived radical intermediate, similar to manganese porphyrinmediated hydroxylation reactions. The chlorination reaction may beexpanded to bromination simply by replacing NaOCl with NaOBr. Thebromination of cyclohexane provided cyclohexyl bromide as the mainproduct with insignificant amounts of cyclohexyl chloride, indicatingthat the hypohalite is the halogen source rather than the solvent or theaxial ligand.

Representative, Non-Limiting Materials.

Sodium hypochlorite (NaOCl, Aldrich) was standardized spectroscopically(λmax292 nm, ε350M-1 cm-1). Sodium hypobromite was prepared by mixingNaOCl with 10% excess sodium bromide (NaBr, 99.99% Aldrich) and usedimmediately. 5,10,16,20-tetraphenylporphyrinatomanganese(III) chloride[Mn^(III)(TPP)Cl] was purchased from Aldrich.5,10,15,20-tetramesitylporphyrinatomanganese(III) chloride[Mn^(III)(TMP)Cl] was prepared by metallation of tetramesitylporphyrin.Bicyclo[4.1.0]heptane (norcarane) was prepared according to a literaturemethod (Smith, R. D.; Simmons, H. E. Org. Synth. 1961, 41, 72).Dichloromethane (HPLC grade) was distilled from CaH₂. Water wasdistilled and deionized with a Millipore system. Other materials werepurchased of the highest purity from Aldrich and used without furtherpurification.

Instrumentation.

NMR spectra were obtained on a 500 MHz Varian INOVA spectrometer and arereported in ppm using solvent as an internal standard (CDCl3 at 7.26ppm). GC/MS analyses were performed on an Agilent 7890A Gaschromatograph equipped with an Agilent 5975 mass selective detector.Internal standards were used for quantification by measuring therelative response factors.

Catalytic Chlorination of Simple Hydrocarbons.

Exemplary simple substrates (i.e., carbon containing compounds) arelisted in Table 1, below, and the method exemplified here may beutilized with other substrates. Under a nitrogen atmosphere, 2 mL NaOCl(0.33 MpH=11) was added to a solution of manganese porphyrin (0.013mmol), tetrabutylammonium chloride (TBACl, 0.027 mmol), and substrate (2mmol) in 1 mL dichlormethane in a 4 mL sealed vial. The biphasic mixturewas stirred smoothly under nitrogen. Reactions were run at ambienttemperature and completion of the reaction was indicated bydisappearance of the brown red color of high valent porphyrin andformation of the green color of manganese(III) species. The catalystswere removed by a short silica gel column eluted by CH₂Cl₂ and thesolution was analyzed by GC/MS. Yields of chlorinated products werecalculated based on oxidant added. The assignment of the products wasbased on the comparison of GC retention times and fragmentation withauthentic samples.

TABLE 1 Halogenation of simple hydrocarbons^(a)

Substrate Product Yield^(b) 1

69%, 57% 2

74% 3

38%   4^(c)

31% 5

12%, 28%  6^(d)

49% ^(a)Standard conditions: Substrate/oxidant/1/PTC = 300:100:2:4.^(b)Yield based on oxidant. Yield determined by GC. ^(c)Mn(TMP)Cl wasused as catalyst. ^(d)NaOBr, prepared by treatment of NaOCl with aslight excess of NaBr, was used as the oxidant.

Example 2 Chlorination of Trans-Decalin

The chlorination of trans-decalin catalyzed by Mn(TPP)Cl or Mn(TMP)Clwas very revealing. With commonly employed chlorinating agents such asN-chlorosuccinimide (NCS) or hypochlorous acid, this substrate providesa mixture of products with poor regioselectivity and tertiary/secondaryselectivities of ˜1.4 and ˜3, respectively. Significantly, chlorinationof trans-decalin with Mn(TPP)Cl as the catalyst provided 95% selectivityfor methylene-chlorinated products (Scheme 1, below). Furthermore, whenthe more hindered catalyst Mn(TMP)Cl was used, 2-chlorodecalins (3a,below) were obtained with 76% selectivity. Such a high selectivity forchlorination of unactivated methylene C—H bonds has not been observedbefore.

The products of trans-decalin chlorination were assigned by comparingthe GC retention time with authentic samples, prepared by treatingcorresponding alcohols with thionyl chloride. The ratio of equatorialand axial isomers was ˜1 for both C1 and C2 chlorination.

Scheme 1: Chlorination of trans-Decalin

yield distribution Mn(TPP)Cl/NaOCl 55% 38% 58% 4% Mn(TMP)Cl/NaOCl 51%76% 19% 5%

Example 3 Methods for Halogenating Complex Substrates

Referring to FIGS. 1A and 1B, example methods for halogenating complexsubstrates are illustrated. An exemplary complex substrate may be5α-cholestane but the method herein may be utilized with othersubstrates. The chlorination of 5α-cholestane, a saturated steroid thatcontains 48 unactivated C—H bonds, was examined.

Remarkably, despite six tertiary C—H bonds and 13 possible methylenesites of chlorination, chlorination was only observed at the C2 and C3positions, the least sterically hindered methylene positions in theA-ring, in a net 55% yield. Referring to FIG. 1A, the C2 chlorinationafforded a 15:1 selectivity for the equatorial chloride (4a in FIG. 1A),while a mixture of epimers was found at C3 (4b in FIG. 1A). This examplehighlights the capacity of steric factors to produce high selectivityfor the chlorination of secondary C—H bonds in a simple, intermolecularevent.

5α-cholestane chlorination: Under a nitrogen atmosphere, 2 mLNaOCl(0.33M pH=11) was added to a solution of Mn(TMP)Cl (0.033 mmol),tetrabutylammonium chloride (TBACl, 0.027 mmol), cholestane (0.22 mmol)in 1 mL dichloromethane in a 4 mL sealed vial. The biphasic mixture wasstirred smoothly under nitrogen. The aqueous layer was removed after 12h and another equiv of fresh hypochlorite was added under N₂. Thereaction was run for another 12 h and the crude mixture was analyzed by¹H NMR.

The Mn(TPP)Cl catalyzed chlorination of cholestane resulted in a morecomplex product mixture. Significantly, the ratio of equatorial to axialC2 chloride was approximately 1:1 compared to 15:1 for Mn(TMP)Cl,suggesting that a porphyrin species is involved in the halogen transferstep.

Sclareolide is a plant-derived terpenoid with antifungal and cytotoxicactivities. Referring to FIG. 1B, the Mn(TMP)Cl catalyzed chlorinationof sclareolide afforded a 42% isolated yield of the C2 equatorialchloride (5a in FIG. 1B). The structure was confirmed by observing thesignature triplet of triplets at δ 4.22 (J) 12.1, 4.2 Hz) in the ¹H-NMRof 5a. The C2/C3 selectivity was 7:1. The method may be extended to anycomplex substrate.

Sclareolide chlorination: The procedure is similar to the cholestanechlorination described above, with the exception that products werepurified by flash chromatography (5% EtOAc/hexanes) and startingmaterial was recycled twice. The assignment of the major product wasbased on the unique ¹H NMR coupling pattern of the axial C2 proton H_(a)at δ 4.22, which displayed one large (anti) and one small (gauche)J-value (triplet of triplets). ¹H NMR (500 MHz, CDCl₃) δ 4.22 (tt,J=12.1, 4.2 Hz, 1H), 2.43 (dd, J=15.5, 14.8 Hz, 1H), 2.27 (dd, J=16.1,6.5 Hz, 1H), 2.10 (dt, J=12.0, 3.4 Hz, 1H), 2.05-1.96 (m, 3H), 1.90 (dq,J=14.3, 3.7 Hz, 1H), 1.70 (td, J=12.6, 4.2 Hz, 1H) 1.55-1.33 (m, 6H),1.12 (dd, J=9.9, 2.8 Hz, 1H), 0.96 (s, 3H), 0.96 (s, 3H), 0.89 (s, 3H).

Regioselective chlorinations of unactivated methylene C—H bonds arerare, with the few known examples involving the use of internaldirecting groups. In the examples herein, the regioselectivity mayderive from intermolecular interactions, rather than structurallyenforced positioning of the catalyst.

A possible mechanism for this new transformation is outlined in Scheme2, below. While the details are yet to be elucidated, only theO═Mn^(IV)—OH porphyrin or a very similar species were observed duringcatalysis. Further, the C—H selectivity depended upon the nature of theporphyrin meso-substituent. It is expected that basic sodiumhypochlorite will oxidize the starting Mn^(III) porphyrin to a dioxo- oroxohydroxoMn^(V) complex. Subsequent hydrogen atom abstraction from thesubstrate would afford an alkyl radical and a hydroxoMn^(IV) complex.For the product-forming step, it is suggested that a chlorine atomtransfer from the L-Mn^(IV)—OCl complex to the incipient carbon radicalcenter also regenerating the reactive oxoMn^(V) species. For this chainreaction to work, the initially formed alkyl radical must escape the[L-Mn^(IV)-OH.R] cage, as evidenced by the rearrangement accompanyingthe chlorination of norcarane. It is expected that a second ligatinghydroxide, or hypochlorite anion, would lower the redox potential of theL-Mn^(IV)-OH intermediate under these basic conditions (pH 12 in theaqueous phase), thus slowing down the rebound rate of the alkyl radicaland preventing the formation of the oxygenated products. Other axialligands such as pyridines led to a loss of the selectivity forhalogenation. Further, the formation of Mn^(IV) porphyrin species duringC—H oxygenation reactions has been noted recently at high pH.

The preference for the least hindered methylene position is attributedto intermolecular nonbonded catalyst-substrate interactions resultingfrom the approach of the sissile C—H bond to the Mn^(v)═O(dπ-pπ)*frontier orbital. A collinear [Mn^(v)═O—H—C] transition state geometrywith σ-symmetry would not explain this obvious preference for methylenesites, whereas a bent, π-approach for H-atom abstraction would result insignificant interactions between the meso-aryl groups of theMn-porphyrin catalyst and steric bulk flanking the substrate C—H bond.

The results demonstrate that highly regioselective aliphatichalogenations can be achieved predictably with catalysts as simple asMn(TPP)Cl and Mn(TMP)Cl and halogenating agents as ubiquitous ashypochlorite or hypobromite. OxoMn^(V) species can also oxygenatehalogen ions and similar halogenations may be accessible with otheroxidants.

Example 4 Additional Substrates for Halogenation

A variety of useful substrates could be halogenated with the method ofhalogenating provided herein. In the exemplary, non-limiting substratesbelow, the hydrogen indicated by an arrow may be replaced by a halogen.A hydrogen on positions adjacent to the arrows may also be replaced withhalogen. The halogen may be a fluorine, chlorine or bromine.

Exemplary simple substrates are listed above, and the method exemplifiedhere may be utilized with other substrates. Under a nitrogen atmosphere,NaOCl (0.1-3 M, pH=9-13) could be added to a solution of manganeseporphyrin (0.001-1 mmol), tetrabutylammonium chloride (TBACl, 0.005-0.5mmol) and substrate (0.1-20 mmol) in dichlormethane in a sealed vial.The biphasic mixture could be stirred smoothly under nitrogen. Reactionscould be run at ambient temperature and completion of the reaction maybe indicated by disappearance of the brown red color of high valentporphyrin and formation of the green color of manganese(III) species.The catalysts may be removed by a short silica gel column eluted byCH₂Cl₂ and the solution analyzed by GC/MS. Yields of chlorinatedproducts could be calculated based on oxidant added. The assignment ofthe products could be based on the comparison of GC retention times andfragmentation with authentic samples.

Example 5 Brominations

Substrates may be brominated by substituting hypochlorite withhypobromite. Likewise, added bromide ion may be oxidized in situ byequivalent amounts of hypochlorite to afford substrate bromination.

Example 6 Fluorinations

Alkyl chlorides and bromides obtained by any method herein can beconverted to alkyl fluorides via nucleophilic substitution usingliterature methods. See, for example, Landini, D., Montanar, R., andRolla, F. “Reaction of Alkyl-Halides and Methanesulfonates with AqueousPotassium Fluoride in Presence of Phase-Transfer Catalysts-FacileSynthesis of Primary and Secondary Alkyl Fluorides” (1974)Synthesis-Stuttgart, Issue: 6, pages: 428-430, which is incorporatedherein by reference as if fully set forth. Such reactions may beprovided in a combination with any method described herein.

Example 7 Manganese Porphyrin Catalyzed Direct C—H OxidativeFluorination

In the presence of mCPBA as oxidant, silver fluoride andtetrabutylammonium fluoride as fluorine source, Mn(TMP)Cl as catalyst,different substrates can be selectively fluorinated. Different cyclicalkanes can be selectively fluorinated with moderate yield. Benzylicposition can be also selectively fluorinated, albeit in a poor butunoptimized yield. Examples are provided in Tables 2 and 3, below.Referring to FIG. 25, a manganese porphyrin-catalyzed reaction scheme isillustrated.

TABLE 2 Simple hydrocarbon fluorination.^(a)

Entry Substrate Product Yield^(b) 1

45% (81%) 2

40% (77%) 3

41% (73%) 4

42% (79%) exo:endo = 5.7:1 5

51% (76%) 1:1.4 6

35% (61%) 7

2:1^(c) ^(a)Reactions run at 70° C. under N₂ in 4:1 CH₃CN/CH₂Cl₂.Substrate:catalyst:oxidant:AgF = 1:0.06:6:2. ^(b)Yields based on totalstarting material determined by GC (yields based on converted startingmaterial in parentheses). ^(c)Identified by the characteristic m-(CH₂F)peak in the mass spectrum.

TABLE 3 Example Fluorinations.

Entry substrates Product Yield 1

45% 2

40% 3

41% 4

42% exo:endo = 5.7:1 5

   51% = 1.4:1 6

21% Yield based on substrate

Intrigued by this unusual fluorination reaction mediated by manganeseporphyrin, the regioselective chlorination with trans-decalin above as amodel substrate was compared to the direct oxidative fluorination of thesame compound. Interestingly, fluorination of this substrate givessimilar regioselectivity as the chlorination reaction, indicating asimilar C—H abstractor. Reaction of trans-decalin under the sameconditions afforded methylene fluorination products with a 3.5 to 1preference for C2 over C1 (FIG. 2A). A reactive oxo- ordioxo-manganese(V) intermediate may be responsible for abstracting ahydrogen in the reaction. Less sterically hindered manganese porphyrincatalysts were less selective.

Fluorination reactions were run under nitrogen with no precautions takento exclude moisture. Solvents were purified according to the method ofGrubbs. (A. B. Pangborn, M. A. Giardello, R. H. Grubbs, R. K. Rosen, F.J. Timmers. Organometallics 15, 1518 (1996), which is incorporatedherein by reference as if fully set forth).5,10,15,20-tetramesitylporphyrinatomanganese(III) chloride[Mn^(III)(TMP)Cl] was prepared by metallation of tetramesitylporphyrin.Iodosylbenzene was prepared by hydrolysis of iodobenzene diacetate withsodium hydroxide solution. Bicyclo[4.1.0]heptane (norcarane) wasprepared according to a literature method. (Smith, R. D.; Simmons, H. E.Org. Synth. 1961, 41, 72, which is incorporated herein by reference asif fully set forth). Other purchased materials were of the highestpurity available from Aldrich and used without further purification.GC/MS analyses were performed on an Agilent 7890A gas chromatographequipped with an Agilent 5975 mass selective detector. ¹H NMR spectrawere obtained on a Varian INOVA 400 (400 Hz) or a Bruker Avance 500 (500MHz) spectrometer and are reported in ppm using solvent as an internalstandard (CDCl₃ at δ 7.26). Data reported as: chemical shift (6 or ppm),multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet),coupling constant (Hz); integrated intensity. Proton decoupled ¹³C NMRspectra were recorded on a Bruker Avance 500 (125 MHz) spectrometer andare reported in ppm using solvents as an internal standard (CDCl₃ at77.15 ppm). ¹⁹F NMR spectra were obtained on a Varian INOVA 400 (375 Hz)spectrometer and are reported in ppm by adding external neat PhF (¹⁹F, δ−113.15 relative to CFCl₃)

General Procedures for Mn(TMP)Cl Catalyzed C—H Bond Fluorinations.

An oven-dried 25 mL Schlenk flask equipped with a magnetic stir bar wascharged with the following: the pre-catalyst, Mn(TMP)Cl (13.2 mg, 0.015mmol, 1 mol %), TBAF.3H₂O (0.3 mmol), AgF (4.5 mmol, 3 equiv.),substrate (1.5 mmol) and naphthalene (internal standard, 0.5 mmol).Under these conditions the UV-vis λ_(max) observed for (TMP)Mn^(III)—Cl(475 nm) changed immediately to that of a 1:2 mixture of (TMP)Mn^(III)-F(453 nm) and [(TMP)Mn^(III)(F)₂]— (440 nm). The flask was capped andpurged with nitrogen for 5 min. Then, CH₃CN (1.5 mL) and CH₂Cl₂ (0.5 mL)were added by syringe and the flask was heated at 50° C. in an oil bath.Iodosylbenzene (6-15 mmol, 4-10 equivalent) was added slowly to thereaction mixture in solid form over a period of 6-15 hours. Significantdecreases in yield were noted when the iodosylbenzene was added rapidly.Much shorter reaction times (1-2 hours) could be achieved at highertemperatures. With mCPBA as the oxidant, up to 40% yields could beobtained within 1 hour. Each addition of 1 equiv. oxidant was followedby Mn(TMP)Cl (13.2 mg, 1 mmol %) added dissolved in minimal amount ofsolvents. When the reaction was completed, the solution was allowed tocool to room temperature and was then passed through a short pad ofsilica gel (washing with dichloromethane). The filtrate was analyzed byGC/MS and then concentrated under vacuum. Products were separated fromthe reaction residue by column chromatography.

Example 8 5α-Androstan-17-One Fluorination (FIG. 26C)

Fluorine-substituted steroids, such as in flumethasone and fluasterone,have been found to be beneficial in blocking metabolic pathways (J. P.Begue, D. Bonnet-Delpon, J Fluorine Chem 127, 992 (2006), which areincorporated herein by reference as if fully set forth) and¹⁸F-fluorodihydrotestosterone has shown promise as a new radiotracer forimaging prostate cancer in man. (P. B. Zanzonico et al. J. Nucl. Med.45, 1966 (2004), which is incorporated herein by reference as if fullyset forth). Since a direct, late-stage steroid fluorination protocolcould greatly extend the applications of these important techniques,application of this manganese-catalyzed fluorination reaction to simplesteroids was sought. The fluorination of 5α-androstan-17-one wasexamined, which contains 30 unactivated sp³ C—H bonds (FIG. 2C).Analysis of this molecule suggested that the carbonyl group wouldelectronically deactivate ring D. Rings B and C are sterically hindered,leaving the methylene groups of A ring as the most likely sites foroxidation. Consistent with this analysis, and despite of the complexityof the molecule, only the C2 and C3 positions in ring A were fluorinatedin a remarkable overall yield of 48% (81% net yield based on 59%conversion). The products of the reactions could be readily assignedfrom the diagnostic ¹⁹F-NMR spectrum and the characteristic protonJ-couplings. Notably, a 5:1 α/β diastereoselectivity was observed forboth C2 and C3 positions, probably reflecting the steric effect of theaxial methyl group at C10.

The reaction was run according to the general procedure above using5α-Androstan-17-one as a substrate. After the reaction was over, themixture was subjected to the workup protocol outlined in the generalprocedure and purified by column chromatography (hexanes and then 30%DCM/hexanes). The assignment of the product structures was based on thediagnostic F-NMR spectrum. 2α (−172.4 ppm, dm), 2β (−172.8 ppm, qt), 3α(−181.5 ppm, qt), 3β (−168.3 ppm, dm).

Example 9 Sclareolide Fluorination

the reaction was run according to the general procedure in Example 7above using sclareolide as a substrate. Sclareolide fluorinationafforded C2 and C3 fluorinated products in a net 56% yield (FIG. 2D).C2-fluorination was favored by nearly 3:1, probably due to the sterichindrance of the gem-dimethyl groups at C4. A similar selectivity hasbeen observed for this substrate by Baran and Eshenmoser forrhodium-catalyzed amination of sclareolide (P. S. Baran, T. Newhouse,Angew Chem Int Edit 50, 3362 (2011); and K. Chen, A. Eschenmoser, P. S.Baran, Angew Chem Int Edit 48, 9705 (2009), which are incorporatedherein by reference as if fully set forth) and by White et al. for aFe(pdp)/H₂O₂ oxidation system. (M. C. White, M. S. Chen. Science 318,783 (2007), which is incorporated herein by reference as if fully setforth). After the reaction was over, the mixture was subjected to theworkup protocol outlined in the general procedure and purified by columnchromatography (hexanes and then 10% EtOAc/hexanes). The assignment ofthe product structures was based on the diagnostic F-NMR spectrum. 2α(−180.3 ppm, dm), 2β (−172.6 ppm, qt), 3α (−187.8 ppm, qt), 3β (−185.6ppm, dm). The major 2α-fluoro isomer could be isolated a white solid ona second column chromatography. ¹H NMR (400 MHz, CDCl₃) δ 4.83 (dtt,J=48.0, 11.3, 4.6 Hz, 1H), 2.45 (dd, J=16.2, 14.7 Hz, 1H), 2.27 (dd,J=15.8, 6.5 Hz, 1H), 2.12-1.85 (m, 6H), 1.70 (td, J=12.6, 4.1 Hz, 1H),1.43-1.30 (m, 6H), 0.99 (s, 3H), 0.95 (s, 3H), 0.89 (s, 3H). ¹⁹F NMR−180.3 ppm. MS (EI) m/z cal'd C₁₆H₂₅FO₂ [M]⁺: 268.2. found 268.2.

Example 10 Bornyl-Acetate Fluorination (FIG. 26D)

the reaction was run according to the general procedure in Example 7above using bornyl acetate as a substrate. After the reaction was over,the mixture was subjected to the workup protocol outlined in the generalprocedure and purified by column chromatography using DCM:hexanes (1:4)as eluent. Reaction of bornyl acetate afforded a 55% isolated yield ofthe exo-5-fluoro-bornyl acetate (FIG. 2B). The characterization of theproduct was based on C—H correlation NMR spectroscopy and ¹⁹F-NMRspectroscopy. (L. F. Lourie et al., J Fluorine Chem 127, 377 (2006),which is incorporated herein by reference as if fully set forth). ¹H NMR(500 MHz, CDCl₃) δ 4.71 (d, J=9.7 Hz, 1H), 4.56 (ddd, J=60, 7.6, 2.3 Hz,1H), 2.33 (m, 1H), 1.98 (s, 1H), 1.63 (dd, J=35.3, 15.4 Hz, 1H), 0.97(s, 3H), 0.85 (s, 3H), 0.83 (s, 3H), 0.68 (dd, J=14.5, 3.4 Hz, 1H). ¹³CNMR (125 MHz, CDCl₃) δ 95.8 (d, 186 Hz), 77.6, 50.5 (d, 17.6 Hz), 37.5(d, 18.0 Hz), 32.2 (d, 11.1 Hz), 21.3, 20.2, 19.4, 12.6. ¹⁹F NMR −158.2ppm. MS (EI) m/z cal'd C₁₂H₁₉FO₂ [M]⁺: 214.1. found 214.1. It wasanticipated that the C5 position of camphor would also be accessible, inanalogy to the selectivity of P450cam (CYP101). (I. Schlichting et al.Science 287, 1615 (2000), which is incorporated herein by reference asif fully set forth). However, treating camphor under the standardfluorination conditions resulted in 95% recovered starting material. Thelow reactivity in this case is attributed to the electron withdrawingcarbonyl group, which apparently deactivates the entire molecule towardfluorination.

The catalytic cycle shown in FIG. 3A is suggested for this manganeseporphyrin catalyzed fluorination. Oxidation of the resting Mn(TMP)Clcatalyst in the presence of fluoride ion could afford a reactiveoxomanganese(V) species, O═Mn^(V)(TMP)F, which then abstracts a hydrogenatom from the substrate to produce a substrate-derived, carbon-centeredradical and a HO—Mn^(IV)-F rebound intermediate. Fluoride binding toseparately prepared Mn^(IV)(O)(TMP) was indicated by a UV spectral shift(423 nm to 427 nm) that was assigned to the formation of[Mn^(IV)(O)(F)(TMP)]—, in analogy to the well-characterized coordinationof hydroxide to Mn^(IV)(O) (J. T. Groves, M. K. Stern. J. Am. Chem. Soc.110, 8628 (1988), which is incorporated herein by reference as if fullyset forth). A step in forming the fluorinated products is capture of theincipient substrate radicals either by HO—Mn^(IV)-F or atrans-difluoro-manganese(IV) species, which forms by reaction with AgF.The unusual methylene selectivity observed in these reactions isattributed to stereoelectronically enforced steric clashes between thesubstrate and the approaching oxoMn^(V) catalyst (FIG. 3B). The LUMOs ina low-spin, d² oxoMn^(V) complex are expected to be the two, orthogonalMn—O π orbitals, which would direct the approach of the scissile C—Hbond into a bent π*-approach trajectory. (Jin, N.; firahim, M.; Spiro,T. G.; Groves, J. T., Trans-dioxo manganese(V) Porphyrins, J. Am. Chem.Soc. 2007, 129, 12416-12418; and Jin, N.; Lahaye, D. E.; Groves, J. T.,A “Push-Pull” Mechanism for Heterolytic 0-0 Bond Cleavage in HydroperoxoManganese Porphyrins, Inorg. Chem. 2010, 24, 11516-11524, which areincorporated herein by reference as if fully set forth).

A number of experiments were conducted to examine this mechanistichypothesis. Initial C—H hydroxylation was ruled out by controls showingthat no fluorides were produced under these conditions with alcohols asstarting materials. Initial C—H hydroxylation was ruled out by controlsshowing that cyclohexanol was oxidized to cyclohexanone under theseconditions. No cyclohexylfluoride was detected. Also, the hydroxyl groupof 1-methylcyclohexanol is stable to the reaction conditions (See entry8 of Table 4, below). Deuterium kinetic isotope effects were evaluatedby the reaction of a 1:1 mixture of cyclohexane and cyclohexane-d₁₂,producing an intermolecular competitive KIE of 6.1. A similar value(5.7) was observed with a mixture of ethylbenzene and ethylbenzene-d₁₅.The large KIE indicates that C—H bond cleavage is the rate-limiting stepin the reaction, consistent with typical manganese porphyrins catalyzedhydroxylation reactions. Furthermore, reaction of norcarane, adiagnostic radical clock substrate, afforded 2-fluoronorcaranes and asignificant amount of the rearranged fluorinated product,3-fluoromethylcyclohexene, that is indicative of a carbon radicalring-opening process (Table 4, entry 6). The 2:1 ratio of thesecyclopropylcarbinyl and homoallyl fluorides indicates a short radicallifetime of 2.5 ns, since the ring-opening rate constant for the2-norcaranyl radical is 2×10⁸ M⁻¹s⁻¹. (J. T. Groves, J Inorg Biochem100, 434 (2006), which is incorporated herein by reference as if fullyset forth). Although a direct reaction between the incipient organicradical and silver fluoride cannot be ruled out at this point, thereaction between phenethyl radical, generated in situ by heatingazo-bis-α-phenylethane with AgF, afforded only a trace amount offluorinated products.

TABLE 4 manganese porphyrin-catalyzed fluorination of simple molecules.Fluorination Major fluorination Minor Entry Substrate product EntrySubstrate product sites 1

7

C4 14% 2

8

C4 12% 3

9

C3 11% 4

10

C2 <2% 5

11

12b, C3 27% cis/trans = 2:1 6

12

C3 9%

A trans-Mn^(IV)(TMP)F₂ (TMP: tetramesitylporphyrin), generated by ligandexchange between a hydroxyl manganese(IV) intermediate and fluoridesource, was postulated to be the key intermediate that transfer fluorineto the carbon radical and make alkyl fluorides. The identification oftrans-difluoroMn^(IV)(TMP) as the likely fluorinating agent was madepossible by its isolation and structural characterization.Trans-Mn^(IV)(TMP)Cl₂, which has been characterized by Gross et al. (L.Kaustov, M. E. Tal, A. I. Shames, Z. Gross, Inorg Chem 36, 3503 (1997),which is incorporated herein by reference as if fully set forth) waschosen as the synthetic precursor of trans-Mn^(IV)(TMP)F₂. TreatingMn^(IV)(TMP)Cl₂ benzene solution with large access AgF (>50 equivalents)would lead to a color change from red to orange red within 30 minutes(FIG. 4). Pure crystals of the Mn^(IV)(TMP)F₂ were obtained by treatingMn^(IV)(TMP)Cl₂ (L. Kaustov, M. E. Tal, A. I. Shames, Z. Gross. Inorg.Chem. 36, 3503 (1997)., which is incorporated herein by reference as iffully set forth) with excess AgF. The molecular structure of this uniquecompound showed two axially bound fluoride ions with F—Mn^(IV)-F bondlengths of 1.7931 (17) and 1.7968 (16) Å (FIG. 3C; Tables 5-9, below).These bond lengths are very close to those of diammoniumhexafluoromanganate(IV), the only other fluoromanganese(IV) species tobe structurally characterized to date. (S. Kaskel, J. Strahle, Z AnorgAllgem Chem 623, 1259 (1997), which is incorporated herein by referenceas if fully set forth). Mn^(IV)(TMP)F₂ could replace silver fluorideunder the fluorination reaction conditions and that thermaldecomposition of azo-bis-α-phenylethane in the presence ofMn^(IV)(TMP)F₂ afforded a 41% yield of 1-fluoroethylbenzene. Further,treatment of Mn^(IV)(O)(TMP) with fluoride ion produced a UV spectralshift (423 nm to 427 nm) assigned to the formation of[Mn^(IV)(O)(F)(TMP)]—, in analogy to the well-characterized coordinationof hydroxide to oxoMn^(IV) (J. T. Groves, M. K. Stern. J. Am. Chem. Soc.110, 8628 (1988), which is incorporated herein by reference as if fullyset forth). These observations indicate that Mn^(IV)(TMP)F₂ or therelated hydroxy-fluoride may be involved in the fluorine delivery stepand that the role of AgF is to replenish the manganese(IV) fluorideduring turnover.

TABLE 5 Crystal data for Mn^(IV)(TMP)F₂ Empirical formula C₆₁H₆₄F₂MnN₄Formula weight  946.10 Temperature 100 K Wavelength Cu Kα radiation, λ =1.54184 Å Crystal system Orthorhombic Space group Pbca Unit Celldimensions a = 23.5969 (3) Å b = 16.1927 (2) Å c = 26.6602 (3) Å Volume10186.8 (2) Å³ Z   8 Density (calculated) 1.234 Mg/m³ Absorptioncoefficient 2.50 mm⁻¹ F(000)  4008 Crystal size 0.17 × 0.10 × 0.05 mmTheta range for data collection 3.7 to 65.6° Index ranges h = −26→27, k= −18→14, l = −31→20 Reflection collected 38219 Independent reflections8519 [R_(int) = 0.029] Absorption correction multi-scan SADABS V2008/1(Bruker AXS)

TABLE 6 Structural refinement details for Mn^(IV)(TMP)F₂ Refinement onF² Least-squares matrix: full R[F² > 2σ(F²)] = 0.052 wR(F²) = 0.157 S =1.07 Data completeness = 0.958 8519 reflections 614 parameters 3restraints Least-squares matrix: full Primary atom site location:structure-invariant direct methods Secondary atom site location:difference Fourier map Hydrogen site location: inferred fromneighbouring sites H-atom parameters constrained w = 1/[σ²(F_(o) ²) +(0.0739P)² + 11.7278P] where P = (F_(o) ² + 2F_(c) ²)/3 (Δ/σ)_(max) =0.001 Δ 

 _(max) = 0.69 e Å⁻³ Δ 

 _(min) = −0.55 e Å⁻³The X-ray structure was of high quality.

The potential energy landscape and electronic structures of theintermediates and transition states proposed in FIGS. 3A-3D wereexplored using DFT and a polarizable continuum solvation model. Fluorineatom transfer from Mn(THP)F₂ to a cyclohexyl radical in the equatorialconfiguration was predicted to occur with a surprisingly low activationbarrier of only 3 kcal/mol, very similar to the oxygen rebound barrierfor hydroxylation reactions catalyzed by oxomanganese porphyrins. Aslightly higher transition state was located for delivery of fluorine toa cyclohexyl radical in an axial configuration (4.2 kcal/mol). Further,the calculated barrier for fluorine transfer was ˜3 kcal/mol lower forthe trans-difluoroMn^(IV) species (X═F) than for the analogoushydroxy-fluoride (X═OH). Thus, the manganese(IV) difluoride should reactmuch faster with cyclohexyl radicals than its hydroxo-fluoro congener.Consistent with this low barrier for fluorine transfer, the transitionstate is very early in the reaction trajectory, showing an exceedinglylong C—F distance of 2.48 Å and a Mn—F distance that is only veryslightly elongated from the starting the manganese(IV) difluoride.

UV-vis spectrum showed that a new species with intense absorption around420 nm, following two weaker absorptions at 520 and 680 nm appeared(FIG. 5A, upper MnTMPCl₂, lower MnTMPCl₂+AgF After 40 Min.). The EPRspectrum of the new species was shown in FIG. 5B (upper, experimentalspectrum; lower, simulated spectrum). A strong signal at g≈4 and weakersignal at g≈2 is consistent with the characteristics of a high-spin d³ion with a large zero-field-splitting (ZFS) constant in an environmentof axial symmetry. The six-line hyperfine splitting caused by I=5/2 ⁵⁵Mnnucleus display at both g≈4 and g≈2 regions. Further triplet splittingwas observed at g≈4 region, suggesting the existence of two fluorides asthe axial ligands, since I=1/2 ¹⁹F nucleus was known to give apparentsuperhyperfine splitting in EPR spectroscopy. (Thuesen, C. A.; Barra, A.L.; Glerup, J. Inorg. Chem. 2009, 48, 3198, which is incorporated hereinby reference as if fully set forth). The crystal structure of this newcomplex was acquired (FIG. 3C). Referring to FIG. 3D, selected bondlengths and angles of trans-Mn^(IV)(TMP)F₂ are illustrated. The bondlength between the manganese and the axial ligands are 1.797 and 1.794 Årespectively, which is very similar to the Mn—F bond length ofK₂Mn^(IV)F₆ (1.79 Å). (Bukovec, P.; Hoppe, R. J. Fluorine Chem. 1983,23, 579, which is incorporated herein by reference as if fully setforth). The visible spectrum of the reaction mixture was complex,apparently due to the presence of several forms of the catalyst duringturnover. However, the good yield of 1-fluoroethylbenzene from thegeneration of phenethyl radical in the presence of Mn(TMP)F₂ providesexperimental support for these computational predictions thatmanganese(IV) fluorides are excellent radical fluorinating agents.

Referring to FIG. 28, the EPR spectra of (X)₂MN^(IV)TMP complexes isillustrated. The spectra demonstrate the presence of the rate 4+species, which is effective as a catalyst herein.

The results described herein show selective fluorination of simplehydrocarbons, terpenoids and steroid derivatives. The yields aresufficiently high and the techniques sufficiently simple that thereaction can be performed without specialized apparatus or complicatedprecautions, other than normal care that should be taken whenever strongoxidants or fluoride-containing reagents are used. Given that the sourceof fluorine in this one-step, one-pot protocol is fluoride ion, thesetechniques may be readily applied to the incorporation of ¹⁸F into awide variety of biomolecules and synthetic building blocks. Moreover,the isolation and structural characterization of thetrans-difluoromanganese(IV) porphyrin, Mn^(IV)(TMP)F₂, suggest theexistence of a rich chemistry of such transition metal fluorides fordelivery of fluorine substituents.

The fluorine transfer ability of trans-Mn^(IV)(TMP)F₂ was tested usingα-azobis-phenylethane as substrate (FIG. 10). Under 105° C., thecorresponding alkyl fluorides can be made within 2 min with 60% yield,with the changing of trans-Mn^(IV)(TMP)F₂ to Mn^(III)(TMP)F. Thecomputational study supports this observation, as it showed that theenergy barrier of fluorine transfer from Mn^(IV)(THP)F₂ (THP:tetrahydroporphyrin) to a secondary alkyl radical was only 3 kcal/mol.Referring to FIG. 6, the fluorine transfer of trans-Mn^(IV)(TMP)F₂ toalkyl radical is illustrated.

A variety of simple alkanes and substituted alkanes, as well as largernatural product molecules, can be fluorinated effectively in thepresence of catalytic amounts of the bulky manganese porphyrin,Mn(TMP)Cl. This oxidative aliphatic fluorination reaction is driven byiodosylbenzene as the oxo-transfer agent, using silverfluoride/tetrabutylammonium fluoride trihydrate as the fluoride source,both in stoichiometric excess. The excess of iodosylbenzene typicallyused in metalloporphyrin oxidations is due to the competingdisproportionation of this reagent, which produces unreactiveiodoxybenzene. The requirement for excess fluoride ion appears to derivefrom the stoichiometry of the fluorination reaction, which also produceshydroxide ions. AgF converts Mn—OH to Mn—F species and Ag₂O. Ultra-dryconditions are not required. Results for the initial exploratoryreactions of a panel of simple substrates are presented in Table 4.Cycloalkanes afforded mono-fluorinated products in ˜50% yield.Typically, conversions were ˜70% with small amounts (15-20%) of alcoholsand ketones also being produced. No products were detected in controlexperiments that omitted the manganese porphyrin or iodosylbenzene,whereas a ˜2:1 ratio of oxygenated to fluorinated products was formed inthe absence of tetrabutylammonium fluoride. Only oxygenated productswere formed without silver fluoride. The benefit of both AgF andtetrabutylammonium fluoride apparently derives from the limitedsolubility of AgF in the reaction medium and the need for a higherfluoride ion concentration than can be maintained by AgF alone. TheUV-vis λ_(max) observed for (TMP)Mn^(III)—Cl (475 nm) changedimmediately to that of a mixture of (TMP)Mn^(III)—F (453 nm) and[(TMP)Mn^(III)(F)₂]— (440 nm) under the reaction conditions.

There were negligible amounts of difluorides produced at this level ofconversion, probably due to the electron deficiency of the productsinduced by the fluorine atom. The high selectivity for monofluorination,the low reactivity of C—H bonds near carbonyl groups and the limitedreactivity of the solvents as well as the tetrabutylammonium ion seem toreflect a very strong polar effect in the C—H bond cleavage step in thisreaction.

A preliminary investigation of the substrate scope led to the resultsshown in Table 4 (entries 7-12). A range of substituted molecules,including ester, tertiary alcohol, ketone and amide substituents, provedto be good substrates for fluorination with Mn(TMP)Cl. Fluorination ofmethyl cyclohexylcarboyxlate (entry 7) and methyl cyclohexanol (entry 8)afforded trans-C3 fluorides as the major products. Mono-substituted fiveand seven-membered cycloalkanes (entries 9, 10, 12) were fluorinatedexclusively at the C3 and C4 positions, respectively, suggesting subtlestereoelectronic effects on the selectivity of this reaction.

Having demonstrated that it is possible to redirect manganese-catalyzedhydroxylation to fluorination, we next aimed to apply this reaction tolarger molecules. The reaction of trans-decalin under the sameconditions afforded methylene monofluorination products with a 3.5 to 1preference for C2 over C1 in an overall 51% yield and a 75% conversion(FIG. 26A). Very high methylene regioselectivity was observed for thissubstrate (>95%), similar to that observed for the manganese-catalyzedchlorination reaction we have recently reported, (Liu, W.; Groves, J.T., Manganese Porphyrins Catalyze Selective C—H Bond Halogenations, J.Am. Chem. Soc. 2010, 132, 12847-12849, which is incorporated herein byreference as if fully set forth) suggesting that a similar reactive oxo-or dioxo-manganese(V) intermediate (Jin, N.; firahim, M.; Spiro, T. G.;Groves, J. T., Trans-dioxo manganese(V) Porphyrins, J. Am. Chem. Soc.2007, 129, 12416-12418, which is incorporated herein by reference as iffully set forth) is responsible for the hydrogen abstraction step inboth reactions.

Stoichiometric amounts of Mn^(IV)(TMP)F₂ could replace silver fluoridein a single-turnover C—H fluorination of cyclooctane using Mn(TMP)Cl andiodosylbenzene. A 43% yield of cyclooctyl fluoride was obtained based onadded Mn^(IV)(TMP)F₂. Thermal decomposition of azo-bis-α-phenylethane togenerate the phenethyl radical in the presence of Mn^(IV)(TMP)F₂ led toa 41% yield of 1-fluoroethylbenzene. These observations indicate thatafter initial hydrogen abstraction, Mn^(IV)(TMP)F₂ can trap thesubstrate radicals in the fluorine delivery step (FIG. 3A). The moderatefluorination yields from these radical trapping experiments are probablydue to the falling concentration of the manganese(IV) difluoride underthese conditions. Crucial roles for silver fluoride in this scenariounder catalytic conditions are first to convert the added Mn(TMP)Cl tothe manganese(III) fluoride form of the catalyst and then to replenishthe inventory of manganese(IV) fluoride during turnover. Although adirect reaction between the substrate radicals and AgF might also beconsidered, the reaction between AgF and phenethyl radicals generated insitu from azo-bis-α-phenylethane afforded only trace amounts offluorinated products.

Example 11 Fluorination of Hydrocarbons (Table 4 Entry 1-5, FIG. 3A)

The reaction was run according to the general procedure above using thehydrocarbon listed as the substrate. When the reaction was completed,the solution was allowed to cool to room temperature and was then passedthrough a short pad of silica gel (washing with dichloromethane). Thefiltrate was analyzed by GC/MS. The assignment of the products was basedon the comparison of GC retention time and mass fragmentation with theauthentic samples. The products of trans-decalin fluorination wereassigned by comparing the GC retention time with authentic samples,prepared by treating corresponding alcohols with DAST.

Example 12 Fluorination of Norcarane (Table 4 Entry 6)

The reaction was run according to the general procedure in Example 7above using bicyclo[4.1.0]heptane (norcarane) as a substrate (2) and 0.5equiv. iodosylbenzene as the oxidant. When the reaction was completed,the solution was allowed to cool to room temperature and was then passedthrough a short pad of silica gel (washing with dichloromethane). Thefiltrate was analyzed by GC/MS. The rearranged product,3-fluoromethylcyclohexene, was identified by the characteristic m-CH₂Fpeak in the mass spectrum.

Example 13 Kinetic Isotope Effect of the Fluorination Reaction

The reaction was run according to the general procedure in Example 7above using cyclohexane/cyclohexane-d₁₂ (1:1) orethylbenzene/ethylbenzene-d₁₀ (1:1) as the substrate and 0.5 equiv.iodosylbenzene as the oxidant. When the reaction was completed, thesolution was allowed to cool to room temperature and was then passedthrough a short pad of silica gel (washing with dichloromethane). Thefiltrate was analyzed by GC/MS. The kinetic isotope effect wasdetermined by calculating the ratio of corresponding peak intensities(82/92 [M-HF]⁺ for cyclohexane/cyclohexane-d₁₂ and 105/114 [M-F]⁺ forethylbenzene/ethylbenzene-d₁₅).

Preparation of Mn^(IV)(TMP)F₂

Mn^(IV)(TMP)F₂ was prepared by treating Mn^(IV)(TMP)Cl₂, prepared aspreviously reported (P. B. Zanzonico et al., J Nucl Med 45, 1966 (2004),which is incorporated herein by reference as if fully set forth), withexcess silver fluoride. In a typical experiment, silver fluoride (1.6mmol) was added in solid form to a solution of Mn^(IV)(TMP)Cl₂ (30 mg,0.033 mmol) in 1.5 mL benzene. The reaction was stirred vigorously atroom temperature. After 2 hours, the solution was filtered to remove theinsoluble silver salts, and the filtrate was concentrated under vacuum.The purple solid thus obtained was redissolved in 0.5 mL of benzene andthe solution was filtered again. The solvent was removed under vacuum toafford Mn^(IV)(TMP)F₂ as a purple solid (24 mg, 84% yield). The shinypurple crystals suitable for X-ray crystal structure analysis were grownby the diffusion of a pentane layer (3 mL) into 0.5 mL benzene solutionat 2° C. (Tables 5-6.

Example 14 Reaction of Azo-Bis-α-Phenylethane with Mn^(IV)(TMP)F₂

The thermal decomposition of azo-bis-α-phenylethane was conducted at105° C. in the presence of freshly prepared Mn^(IV)(TMP)F₂. In a typicalexperiment, silver fluoride (1.6 mmol) was added in solid form to asolution of Mn^(IV)(TMP)Cl₂ (30 mg, 0.033 mmol) in 1.5 mL benzene-d₆.The reaction mixture was stirred vigorously at room temperature. After 2hours, the solution was filtered into a 4 mL vial, andazo-bis-α-phenylethane (3 mg, 0.4 equiv) was added to the filtrate. Thesolution was degassed by three freeze-pump-thaw cycles and was thenheated at 105° C. for 4 min. The vial was then cooled to roomtemperature and the yield of (1-fluoroethyl)benzene was determined by¹⁹F NMR (δ, −167.2 ppm) using trifluorotoluene as the internal standard.

Example 15 Single Turnover Fluorination of Cyclooctane withMn^(IV)(TMP)F₂

The single turnover fluorination reaction was carried out in thepresence of Mn(TMP)Cl with Mn^(IV)(TMP)F₂ in place of silver fluoride.In a typical experiment, an oven-dried 25 mL Schlenk flask equipped witha magnetic stir bar was charged with the following: Mn(TMP)Cl (30 mg,0.034 mmol), TBAF.3H₂O (0.3 mmol) and Mn^(IV)(TMP)F₂ (30 mg, 0.034 mmol.The flask was capped and purged with nitrogen for 5 min. Then, CH₃CN(1.5 mL) and CH₂Cl₂ (0.5 mL) containing cyclootane (1.5 mmol) were addedvia syringe and the flask was heated at 50° C. in an oil bath.Iodosylbenzene (11 mg, 0.05 mmol) was added in one portion to themixture and the reaction was stirred for 30 minutes. The solution wasallowed to cool to room temperature and was then passed through a shortpad of silica gel (washing with dichloromethane). The filtrate wasanalyzed by GC/MS and the yield of cyclooctyl fluoride (43%) wascalculated based on Mn^(IV)(TMP)F₂ loaded using ethylbenzene as aninternal standard. There was negligible fluorination under theseconditions without Mn^(IV)(TMP)F₂.

Example 16 Table 4, Entry 7, Compound 8

The reaction was run according to the general procedure in Example 7above using methyl cyclohexanecarboxylate as the substrate. Purificationby column chromatography (hexanes and then 5% EtOAc/hexanes). Theregiochemical assignment was made on the basis of the unsymmetrical ¹³CNMR. The stereochemical assignment was made on the basis of the obviousvicinal, trans-diaxial H—F J-coupling and small vicinal H—H couplings (δ4.85, dtt, J=47.7, 5.7, 2.3 Hz). ¹HNMR (500 MHz, CDCl₃) δ 4.85 (dt,J=47.7, 2.3 Hz, 1H), 3.61 (s, 3H), 2.67 (tt, J=11.6, 3.8 Hz, 1H), 2.11(m, 1H), 1.89 (m, 2H), 1.72-1.38 (m, 5H). ¹³C APT NMR (125 MHz, CDCl₃)176, 88.6, 51.8, 37.8, 33.1, 30.2, 28.1, 19.6 ppm. ¹⁹F NMR −183.0 ppm.MS (EI) m/z cal'd C₈H₁₃FO₂ [M]⁺: 160.1. found 160.1.

Example 17 Table 4, Entry 8, Compound 9

The reaction was run according to the general procedure in Example 7above using methyl cyclohexanol as a substrate. Purification by columnchromatography (hexanes and then 10% ethyl acetate/hexanes). Theregiochemical assignment was made on the basis of the unsymmetrical ¹³CNMR. The stereochemical assignment was made on the basis of the obviousJ-coupling between the fluorine and the hydroxyl proton, δ 2.50 (d,J=10.7 Hz). ¹HNMR (500 MHz, CDCl₃) δ 4.86 (dtt, J=48.1, 5.3, 2.9 Hz,1H), 2.50 (d, J=10.7 Hz, 1H), 1.97 (m, 1H), 1.84 (m, 2H), 1.64 (m, 2H),1.41 (m, 3H), 1.14 (s, 3H). ¹³C NMR (125 MHz, CDCl₃) 91.6, 42.8, 38.4,30.4, 29.7, 16.7 ppm. ¹⁹F NMR −179.2 ppm. MS (EI) m/z cal'd C₇H₁₃FO[M]⁺: 132.1. found 132.1.

Example 18 Table 4, Entry 9, Compound 10

The reaction was run according to the general procedure in Example 7above using methyl cycloheptanone as a substrate. Purification by columnchromatography (hexanes and then 4% ethyl acetate/hexanes). Theregiochemical assignment was made on the basis of the three-bond F—C₂coupling, 36.4 ppm (d, J=8.7 Hz). ¹HNMR (500 MHz, CDCl₃) δ 4.75 (dtt,J=45.6, 7.4, 2.7 Hz, 1H), 2.73, (m, 1H), 2.49, (m, 1H), 2.40 (m, 1H),2.30 (ddd, J=15.4, 9.2, 2.5 Hz, 1H), 2.08-1.76 (m, 5H). 1.58 (m, 1H).¹³C APT NMR (125 MHz, CDCl₃) 91.7, 43.5, 36.4, 35.4, 29.7, 17.6 ppm. ¹⁹FNMR −175.3 ppm. MS (EI) m/z cal'd C₇H₁₁FO [M]⁺: 130.1. found 130.1.

Example 19 Table 4, Entry 10, Compound 11

The reaction was run according to the general procedure in Example 7above using N-methyl-trifluoroacetylcyclopentylamine as the substrate.Purification by column chromatography (hexanes and then 4% ethylacetate/hexanes). The regiochemical assignment was made the on the basisof the two-bond F—C₂ coupling, 36.7 ppm (d, J=22.0 Hz). Thestereochemical assignments were made on the basis of the ¹⁹FNMR chemicalshifts. The cis-isomer (−171.0 ppm) exhibits a smaller upfield shiftthan the trans-isomer (168.8) due to the shielding of the fluorine bythe amide group. For trans-11: ¹HNMR (500 MHz, CDCl₃) δ 5.13-4.39 (m,2H), 2.93 (d, 3H), 2.23 (dddd, J=35.8, 15.9, 10.6, 5.0 Hz, 1H), 2.07 (m,1H), 1.96-1.71 (m, 3H), 1.67-1.49 (m, 1H). ¹³C APT NMR (125 MHz, CDCl₃)157.2, 116.5, 94.5, 56.4, 54.0, 36.7, 35.5, 32.9, 29.0, 27.5, 25.8 ppm.¹⁹F NMR −68.7 (s), −70.2 (s), −168.8 (m) ppm. MS (EI) m/z cal'd C₇H₁₁FO[M]⁺: 213.1. found 213.1.

Example 20 Table 4, Entry 11, Compound 12a (Cis)

The reaction was run according to the general procedure in Example 7above using cyclohexylacetate as a substrate. Purification by columnchromatography (1% ethyl acetate/petroleum ether). The regiochemicalassignment was made the on the basis of the symmetric ¹³C NMR. Thestereochemical assignment was made on the basis of the obvious vicinal,trans-diaxial H—F J-coupling and the small vicinal H—H coupling, δ 4.63(dtt, J=52.1, 5.8, 2.9 Hz). ¹H NMR (500 MHz, CDCl₃) δ 4.75-4.57 (m, 2H),1.99 (s, 3H), 1.93 (m, 2H), 1.74 (m, 2H), 1.68-1.57 (m, 4H). ¹³C APT NMR(125 MHz, CDCl₃) 170.7, 88.7, 70.6, 28.9 26.6, 21.5 ppm. ¹⁹F NMR −180.4ppm. MS (EI) m/z cal'd C₈H₁₂O₂ [M-HF]⁺: 140.1. found 140.1.

Example 21 Table 4, Entry 11, Compound 12b (Cis)

The regiochemical assignment was made the on the basis of theunsymmetrical ¹³C NMR. The stereochemical assignment was made on thebasis of the H—F J-coupling and the large vicinal H—H coupling, δ 4.48(dtt, J=48.0, 10.1, 4.4 Hz, 1H). ¹H NMR (500 MHz, CDCl₃) δ 4.65 (m, 1H),4.48 (dtt, J=48.0, 10.1, 4.4 Hz, 1H), 2.28 (m, 1H), 2.04-1.93 (m, 2H),1.98 (s, 3H). 1.81 (m, 2H), 1.60-1.40 (m, 3H), ¹³C APT NMR (125 MHz,CDCl₃) 170.5, 89.5, 69.9, 37.9, 31.5, 30.5, 21.4, 18.8 ppm. ¹⁹F NMR−180.4 ppm. MS (EI) m/z cal'd C₈H₁₂O₂ [M-HF]⁺: 140.1. found 140.1.

Compounds 12a (trans) and Compound 12b (trans) were isolated as aninseparable mixture. ¹H NMR (500 MHz, CDCl₃) δ 5.07-5.46 (m, 2H), 1.97(s, 3H), 1.95-1.32 (m, 8H). ¹⁹F NMR −180.0, −181.1 ppm.

Example 22 Table 4, Entry 12, Compound 13

The reaction was run according to the general procedure above usingcycloheptyl benzoate as the substrate. Purification by columnchromatography (hexanes and then 1% ethyl acetate/hexanes) and productsisolated as a mixture of cis and trans isomers. The regiochemicalassignment was made the on the basis of the three-bond F—C₂ coupling,26.6 ppm (d, J=10.0 Hz). ¹HNMR (500 MHz), CDCl₃) δ 7.96 (m, 2H), 7.49(m, 2H), 7.38 (m, 1H), 5.20-4.70 (m, 2H). 2.50-1.50 (m, 10H). ¹⁹F NMR−164.6, −166.7 ppm. MS (EI) m/z cal'd C₁₄H₁₇FO₂ [M]⁺: 236.1. found236.1.

Example 23 FIG. 26B. Sclareolide Fluorination

Reaction was run according to the general procedure in Example 7 aboveusing sclareolide as a substrate. After the reaction was over, themixture was subjected to the workup protocol outlined in the generalprocedure and purified by column chromatography (hexanes and then 10%EtOAc/hexanes). The assignment of the product structures was based onthe diagnostic F-NMR spectrum. 2α (−180.3 ppm, dm), 2β (−172.6 ppm, qt),3α (−187.8 ppm, qt), 3β (−185.6 ppm, dm). The major 2α-fluoro isomercould be isolated a white solid on a second column chromatography. ¹HNMR (400 MHz, CDCl₃) δ 4.83 (dtt, J=48.0, 11.3, 4.6 Hz, 1H), 2.45 (dd,J=16.2, 14.7 Hz, 1H), 2.27 (dd, J=15.8, 6.5 Hz, 1H), 2.12-1.85 (m, 6H),1.70 (td, J=12.6, 4.1 Hz, 1H), 1.43-1.30 (m, 6H), 0.99 (s, 3H), 0.95 (s,3H), 0.89 (s, 3H); ¹⁹F NMR −180.3 ppm. MS (EI) m/z cal'd C₁₆H₂₅FO₂ [M]⁺:268.2. found 268.2.

Example 24 FIG. 3C. 5α-Androstan-17-One Fluorination

Reaction was run according to the general procedure in Example 7 aboveusing 5α-androstan-17-one as a substrate. After the reaction was over,the mixture was subjected to the workup protocol outlined in the generalprocedure and purified by column chromatography (hexanes and then 30%DCM/hexanes). The assignment of the product structures was based on thediagnostic F-NMR spectrum. 2α (−172.4 ppm, dm), 2β (−172.8 ppm, qt), 3α(−181.5 ppm, qt), 3β (−168.3 ppm, dm). The major product3α-fluoro-5α-Androstan-17-one was isolated by a second columnchromatography (4% ethyl acetate/hexanes). ¹HNMR (500 MHz, CDCl₃) δ 4.75(dm, J=48.7, 2.5 Hz, 1H), 2.37 (dd, J=19.1, 8.9 Hz, 1H), 2.01 (dt,J=19.4, 9.1 Hz, 1H), 1.85 (m, 2H), 1.73 (m, 2H), 1.60 (m, 3H), 1.53-1.32(m, 6H), 1.28-1.09 (m, 6H) 0.95 (m, 1H), 0.79 (s, 3H), 0.74 (s, 3H). ¹³CAPT NMR (125 MHz, CDCl₃) 221.6, 89.4, 54.2, 51.4, 47.8, 39.4, 35.9,35.0, 33.9, 32.4, 31.5, 30.8, 28.0, 27.1, 21.8, 20.1, 13.9, 11.2 ppm.¹⁹F NMR −181.5 ppm. MS (EI) m/z cal'd C₁₉H₂₉FO [M]+: 292.2. found 292.2.

Example 25 FIG. 26D. Bornyl-Acetate Fluorination

Reaction was run according to the general procedure in Example 7 aboveusing bornyl acetate as a substrate. After the reaction was over, themixture was subjected to the workup protocol outlined in the generalprocedure and purified by column chromatography using DCM:hexanes (1:4)as eluent. The product was obtained in 55% yield. Colorless oil. ¹H NMR(500 MHz, CDCl₃) δ 4.71 (d, J=9.7 Hz, 1H), 4.56 (ddd, J=60, 7.6, 2.3 Hz,1H), 2.33 (m, 2H), 2.05-1.95 (m, 1H) 1.98 (s, 3H), 1.63 (dd, J=35.3,15.4 Hz, 1H), 0.97 (s, 3H), 0.85 (s, 3H), 0.83 (s, 3H), 0.68 (dd,J=14.5, 3.4 Hz, 1H). ¹³C APT NMR (125 MHz, CDCl₃) δ5.8 (d, 186 Hz),77.6, 50.5 (d, 17.6 Hz), 37.5 (d, 18.0 Hz), 32.2 (d, 11.1 Hz), 21.3,20.2, 19.4, 12.6 ppm. ¹⁹F NMR −158.2 ppm. MS (EI) m/z cal'd C₁₂H₁₉FO₂[M]⁺: 214.1. found 214.1. The ¹H-NMR splitting pattern of the proton at4.55 (ddd) indicates that the fluorination occurred at a secondarycarbon position adjacent to a methylene group. The ¹³C NMR spectrumdisplays a doublet for the C4 carbon with a coupling constant of 16 Hz,consistent with a 2 J ¹³C—F coupling, which, together with the ¹H NMRdata, clearly designates C5 as the fluorination position. Theexo-fluorine configuration was confirmed by the ¹⁹F-NMR signal at −158ppm, whereas the endo product would have a signal at −190 ppm.

Example 26 Exemplary Fluorinations

Referring to FIGS. 9A-9B, fluorination of N-Phth amantadine isillustrated. Referring to FIGS. 10A-10B, fluorination of N-PhthMemantine is illustrated. Referring to FIGS. 11A-11B, fluorination of2-adamantanone is illustrated. Referring to FIGS. 12A-12B, fluorinationof rimantadine analogue is illustrated. Referring to FIGS. 13A-13B,fluorination of adapalene precursor is illustrated. Referring to FIGS.14A-14B, fluorination of perindopril precursor is illustrated. Referringto FIGS. 15A-15B, fluorination of protected gabapentin is illustrated.Referring to FIGS. 16A-16B, fluorination of methyl octanoate isillustrated. Referring to FIGS. 17A-17B, fluorination of methyl nonanateis illustrated. Referring to FIGS. 18A-18C, fluorination of methylhexanoate is illustrated. Referring to FIGS. 19A-19C, fluorination ofcyclohexyl acetate is illustrated. Referring to FIGS. 20A-20C,fluorination of cyclohexane carboxylic acid methyl ester is illustrated.Referring to FIG. 21, lyrica (pregabalin) with venlafaxin-fluorineintroduced into the cyclohexyl ring at positions C3 and C4 isillustrated. Referring to FIG. 22, fluorine introduced into thesecondary and tertiary positions of the isobutyl substituent isillustrated.

Example 27 Synthesis of Fluoro-Buspirone

The parent drug, Buspirone (brand name Buspar) is a psychoactive drugand pharmaceutical medication of the piperazine and azapirone chemicalclasses. It is used primarily as an anxiolytic, specifically forgeneralized anxiety disorder. Bristol Myers Squibb gained FDA approvalfor buspirone in 1986 for generalized anxiety disorder, and it becameavailable as a generic in 2001. Referring to FIG. 7A, the fluorinatedbuspirone derivative is illustrated. FIG. 7B illustrates thatfluorination of buspirone precursor affords fluorinated product withanother unknown product. Referring to FIG. 7C, the mass spectrum of thefluorinated buspirone peak is illustrated. Referring to FIG. 7D, themass spectrum of the buspirone precursor starting material isillustrated. The fluorinated derivative described here appears to be anew composition of matter. A large proportion of new drugs arefluorinated in particular places both the affect binding to theirtargets and to decrease the incidence of toxic metabolism. This newmethod produces a novel fluorinated derivative of the generic drug.There are at present few if any ways to incorporate fluorine atomsselectively into complex compounds. In this case we have incorporatefluorine into an otherwise inaccessible part of the molecular scaffoldof this drug. The new fluorination technology previously described hasbeen employed to incorporate fluorine either into the immediateanhydride precursor of buspirone and directly into the drug itself. Thefluorine is located in the five-membered ring.

Example 28 Decarboxylative Fluorination Reaction

Since C—H fluorination can also be achieved at room temperature,reaction conditions under room temperature were searched. Cumene-like2-methyl-2-phenylpropanoic acid was chosen as the substrate for reactionoptimization. Initial investigation showed that in the presence ofexcess TBAF (the same as C—H fluorination conditions, about 30 equiv vs.catalyst), white solids would precipitated and the whole reactionsolution became slurry. Accordingly, only trace amounts of fluorinatedproduct could be detected by GC-MS under those conditions. This wasattributed to the deprotonation of carboxylic acids aided by the largeamount of basic TBAF, which then facilitated the formation of silvercarboxylate and prevent the activation of carboxylic acids byoxomanganese porphyrin. The amount of TBAF was then decreased to 5 equivvs. catalyst. Significantly, the yield of fluorination product wasincreased to 18% (based on oxidant, the same below), with 8% ofdesaturation product and less than 1% oxygenated product (FIG. 29).Control experiments omitting the manganese porphyrin showed nodetectable fluorination product by GC-MS, suggesting the crucialimportance of manganese porphyrin catalyst. The decarboxylativefluorination reaction based on the manganese porphyrin system will bevery promising to be a powerful tool of fluorination. It appears thatthe unique and unprecedented manganese(IV) difluoride (Mn(TMP)F₂)isolated and structurally characterized is the fluorinating catalyst.This is the first catalytic decarboxylative fluorination system to bereported to date. The reaction conditions are very mild and the yieldmay be largely increased by further optimized the reaction conditions.

Example 29 Additional Halogenating Catalysts

Additional halogenating catalysts may include additional metal ligandcomplexes. Referring to FIGS. 23A-23D, examples of ligands that willassist C—H fluorination are illustrated. Referring to FIG. 23A, aporphyrin is illustrated. Referring to FIG. 23B a phthalocyanine isillustrated. Referring to FIG. 23C, a porphyrazine is illustrated.Referring to FIG. 23D, a tetra-N-methyl-tetra-2-pyridoporphyrazine isillustrated.

Further examples of ligands that may assist oxidative C—H fluorinationare illustrated in FIGS. 24A-24G. Referring to FIG. 24A anN-pyridylmethyl-tri-aza-cyclononane is illustrated. Referring to FIG.24B, an N,N-dipyridylmethyl cyclohexadiamine is illustrated. Referringto FIG. 24C, a tetra-aza-cyclotetra-decane is illustrated. Referring toFIG. 24D, an N,N-dipyridylmethyl 2,2′-dipyrrolidine is illustrated.Referring to FIG. 24E, an N,N-dipyridylmethyl ethylenediamine isillustrated. Referring to FIG. 24F, a tripyridyl amine (TPA). Referringto FIG. 24G, salen is illustrated. Any one or more of the ligands inFIGS. 23A-24G, along with a metal, may be provided as a fluorinatingcatalyst.

Salen, salophen, phthalocyanine and porphyrazine ligands for manganesemay also be used as a fluorinating catalyst. It was found that in thepresence of a manganese salen (FIG. 29) species as the catalyst,different substrates with benzylic protons can be selectivelyfluorinated. Substrates that have been tested so far are illustrated inFIG. 30. Substrates that are likely to work by analogy are illustratedin FIG. 31. Reactions were run as described for the manganese porphyrincatalyst just substituting the manganese salen catalyst. Generalizedligand structures are illustrated in FIGS. 32 and 33. Referring to FIG.32, a manganese salophen complex is illustrated. Axial ligands and thecounter ion can typically be halide, acetate (or other carboxylicacids), perchlorate, etc. Typical substitutions at carbons b-h can bealkyl, aryl or halogen. Substituents could also be carboxylate,sulfonate or trialkylammonium to afford higher solubility on polarsolvents such as water. Referring to FIG. 33, manganese salen complex(M=Mn) is illustrated. Typical substituent groups can be alkyl, such ast-butyl, or aryl, such as phenyl, or halide. The groups R′ can be alkylor aryl, such as phenyl, in either the cis or trans stereochemicalarrangement. The two R′ groups together with the ethano group can form acycloalkyl substituent such as cyclopentyl or cyclohxyl. The ring fusionin such cases can be cis or trans.

Referring to FIGS. 34-37, trans-difluoro-manganese(IV) complexes for C—Hfluorination are illustrated. Referring to FIG. 34,trans-difluoro-manganese(IV) Salen complexes are illustrated where R canbe alkyl or aryl, and b-f can be alkyl, aryl or halogen. Referring toFIG. 35, trans-difluoro-manganese(IV) Salen complexes are illustratedwhere R can be alkyl or aryl, and b-f can be alkyl, aryl or halogen.Referring to FIG. 36, trans-difluoro-manganese(IV) cyclohxyl-salen isillustrated where b-f can be alkyl, aryl or halogen. Referring to FIG.37, trans-difluoro-manganese(IV) salophen complexes are illustrated,where b-h can be alkyl, aryl or halogen.

Example 30 Additional Substrates

Referring to FIGS. 38 and 39, additional substrates are illustrated thatmay be used in any method contained herein in the form illustrated, oras an analog thereof.

As used herein, a carbon containing compound may also be referred to asa target or substrate. As used herein, an analog of a carbon containingcompound refers to a compound of a similar structure and/or ring systemin which one to several atoms or substituents are substituted for atomsor substituents in the parent structure but retaining the overall shapeof the molecule. In some aspects, an analog may bind to the samebiological target and exert a similar biological activity.

Example 31 Additional Ligands

The phenyl substituent in a tetraphenyl or tetramesityl porphyrin hereincould be naphthyl, and these aryl groups could also have -ethyl,trifluoromethyl, halogen or -nitro substituents attached to the phenylor aryl groups.

The references cited throughout this application are incorporated forall purposes apparent herein and in the references themselves as if eachreference was fully set forth. For the sake of presentation, specificones of these references are cited at particular locations herein. Acitation of a reference at a particular location indicates a manner(s)in which the teachings of the reference are incorporated. However, acitation of a reference at a particular location does not limit themanner in which all of the teachings of the cited reference areincorporated for all purposes.

Any single embodiment herein may be supplemented with one or moreelement from any one or more other embodiment herein.

It is understood, therefore, that this invention is not limited to theparticular embodiments disclosed, but is intended to cover allmodifications which are within the spirit and scope of the invention asdefined by the appended claims; the above description; and/or shown inthe attached drawings.

1. A method of direct oxidative C—H fluorination of a carbon containingcompound having an sp3 C—H bond to form an sp3 C—F bond, the methodcomprising: combining a carbon containing compound having an sp3 C—Hbond, a fluorinating agent, a fluorinating catalyst, and an oxidant,wherein the fluorinating agent is a fluoride ion source.
 2. The methodof claim 1, wherein the carbon containing compound is added in aconcentration from 1 mM to 5 M, the fluorinating agent is added in aconcentration from 1 mM to 5 M, the fluorinating catalyst is added in aconcentration from 1 mol % to 20 mol %, and the oxidant is added in aconcentration from 1 mM to 1 M in each addition.
 3. The method of claim1, further comprising allowing the combined carbon containing compound,fluorinating agent, fluorinating catalyst, and oxidant to react for 30minutes to 12 hours.
 4. The method of claim 1, further comprisingmaintaining the carbon containing compound, the fluorinating agent, thefluorinating catalyst, and the oxidant at a temperature from −20° C. to+100° C.
 5. The method of claim 1, wherein combining further comprises:mixing the fluorinating catalyst, the fluorinating agent, and the carboncontaining compound in a solvent to form a first mixture; providing aninert gas over the first mixture; and adding the oxidant to the firstmixture to form a second mixture.
 6. The method of claim 1, wherein thecarbon containing compound includes a compound selected from the groupconsisting of neopentane; toluene; cyclohexane; norcarane;trans-decalin; 5α-cholestane; sclareolide; 1,3,5(10)-estratrien-17-one;(1R,4aS,8aS)-octahydro-5,5,8a-trimethyl-1-(3-oxobutyl)-naphtalenone;(1R,4S,6S,10S)-4,12,12-trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one;levomethorphan; lupine; 20-methyl-5alpha(H)-pregnane; isolongifolanone;caryophyllene acetate; N-acetyl-gabapentin methyl ester;acetyl-amantidine; phthalimido-amantadine; methyloctanoate; saturatedfatty acid esters; N-acetyl-Lyrica methyl ester; artemisinin, adapalene;finasteride; N-acetyl-methylphenidate; mecamylamine;N-acetyl-mecamylamine; N-acetyl-memantine; phthalimidi-memantine;N-acetyl-enanapril precursor methyl ester; progesterone; artemisinin;adapalene; dopamine derivative; pregabalin; cholestane; finasteride;methylphenidate derivative; mecamylamine; gabapentin; memantinederivative; gabapentin; rimantadine derivative; isoleucine derivative;leucine derivative; valine derivative; pregesterone; tramadol; enalaprilprecursor;(1R,4aS,8aS)-5,5,8a-trimethyl-1-(3-oxobutyl)octahydronaphthalen-2(1H)-one;phenylalanine; donepezil precursor; amphetamine; 6-tocopherol form ofvitamin E; tyrosine; melatonin; tryptophan; estrone acetate;progesterone; dopamine; homophenylalanine; DOPA; ibuprofen methyl ester;buspirone; eticyclidine; memantine; amantadine; lyrica; lubiprostone;penridopril; fosinopril; N-Phth amantadine; N-Phth Memantine;2-adamantanone; rimantadine analogue; adapalene precursor; perindoprilprecursor; protected gabapentin; methyl octanoate; methyl nonanate;methyl hexanoate; cyclohexyl acetate; and cyclohexane carboxylic acidmethyl ester; or an analog of any of the foregoing.
 7. The method ofclaim 1, wherein the carbon containing compound is a drug or drugcandidate precursor.
 8. The method of claim 1, wherein the fluorinatingagent is selected from the group consisting of silver (I) fluoride,silver (II) fluoride, tetrabutyl ammonium fluoride, sodium fluoride,potassium fluoride, silver fluoride and tetra alkyl ammonium fluoride,trialkyl amine trihydrofluoride R₃N(HF)₃, the ammonium salt[R₃NH][H₂F₃], and potassium crown ether fluoride.
 9. The method of claim1, wherein the fluorinating catalyst includes a metal complexed with aligand selected from the group consisting of a porphyrin, aphthalocyanine, a corrole, an N-pyridylmethyl-tri-aza-cyclononane, anN,N-dipyridylmethyl cyclohexadiamine, a tetra-aza-cyclotetra-decane, anN,N-dipyridylmethyl 2,2′-dipyrrolidine, an N,N-dipyridylmethylethylenediamine, a tripyridyl amine (TPA), a salen, a salophen, aphthalocyanine, and a porphyrazine, and (R,R)—Mn(salen)(F2):(R,R)-(−)-N,N′-Bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminomanganese(IV)trans-difluoride.
 10. The method of claim 5, wherein the metal isselected from the group consisting of manganese, copper, vanadium,chromium, iron, cobalt and nickel.
 11. The method of claim 1, whereinthe fluorinating catalyst is a manganese porphyrin, a manganese salen,or a manganese salophen.
 12. The method of claim 11, wherein themanganese porphyrin is selected from the group consisting of Mn(TPP)Cl,Mn(TMP)Cl, Mn^(III)(TPP)C, Mn^(III)(TMP)Cl, Mn^(IV)(TMP)F₂,Mn(III)[tetra-2,6-dichlorophenyl porphyrin, Mn(III) [tetra-2-nitrophenylporphyrin], Mn(III)[tetra-2-naphthyl porphyrin, Mn(III)[pentachlorophenyl porphyrin, Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octachloroporphyrin],Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octabromoporphyrin], and Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octanitroporphyrin.
 13. The method ofclaim 1, wherein the fluorinating catalyst is a manganese complex havingat least one fluoride ligand bound to the manganese and the formulaL₅Mn(IV)—F, where L is selected from the group including oxygen,nitrogen, and halide, and the manganese has octahedral coordination withsix total ligands and a neutral overall charge.
 14. The method of claim1, wherein the fluorinating catalyst is a manganese complex having atleast one fluoride ligand bound to the manganese and the formulaL₅Mn(V)—F, where L is selected from the group consisting of oxygen,nitrogen and halide, and the manganese has octahedral coordination withsix total ligands and a neutral overall charge.
 15. The method of claim1, wherein the fluorinating catalyst is a manganese complex having oneor two fluoride ligands bound to the manganese and the formulaL₅Mn(IV)—F or L₄Mn(IV)—F₂, where L is selected from the group consistingof oxygen, nitrogen and halide, and the manganese has octahedralcoordination with six total ligands and a neutral overall charge. 16.The method of claim 1, wherein the oxidant is selected from the groupconsisting of meta-chloroperoxybenzoic acid (mCPBA), idosylbenzene,peroxyacid, alkyl peroxide, peroxy sulfate(oxone), peroxycarbonate,peroxyborate, iodosyl mesitylene, pentafluoro-iodosylbenzene, benzenedifluoroiodinane [phenyl-IF2], diacetoxyiodobenzene, 2-iodosylbenzoicacid, and peroxyacetic acid.
 17. The method of claim 1, wherein thefluorinating agent includes ¹⁸F and a product produced by the methodincludes ¹⁸F.
 18. A composition comprising at least one compoundselected from the group consisting of 3-fluoro-5a-cholestane; 2- and3-fluoro-sclareolide; 1,3,5(10)-estratrien-17-one;fluoro-(1R,4aS,8aS)-octahydro-5,5,8a-trimethyl-1-(3-oxobutyl)-naphthalenone;(1R,4S,6S,10S)-4,12,12-trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one;fluoro-levomethorphan; fluoro-lupine;fluoro-20-methyl-5alpha(H)-pregnane; fluoro-isolongifolanone;fluoro-caryophyllene acetate; fluoro-N-acetylgabapentin methyl ester;fluoro-acetyl-amantidine; phthalimido-fluoro-amantadine;methylene-fluorinated methyloctanoate; methylene fluorinated saturatedfatty acid esters; N-acetyl-fluoro-Lyrica methyl ester;fluoro-artemisinin, fluoro-adapalene; fluoro-finasteride;N-acetyl-methyl-fluoro-phenidate; fluoro-mecamylamine;N-acetyl-fluoro-mecamylamine; N-acetyl-fluoro-memantine;phthalimido-fluoro-memantine; N-acetyl-fluoro-enanapril precursor methylester; fluoro-progesterone; fluoro-dopamine derivative;fluoro-pregabalin; fluoro-cholestane; methyl-fluoro-phenidatederivative; fluoro-gabapentin; fluoro-memantine derivative;fluoro-rimantadine derivative; fluoro-tramadol; fluoro-enalaprilprecursor; fluoro-donepezil precursor; fluoro-amphetamine;fluoro-tocopherol form of vitamin E; fluoro-melatonin;homophenylalanine; DOPA; fluoro-ibuprofen methyl ester;fluoro-buspirone; fluoro-eticyclidine; fluoro-amantadine;fluoro-lubiprostone; fluoro-penridopril; fluoro-fosinopril;fluoro-2-adamantanone; fluoro-rimantadine analogue; fluoro-adapaleneprecursor; fluoro-perindopril precursor; protected fluoro-gabapentin;methyl fluoro-octanoate; methyl fluoro-nonanate; methylfluoro-hexanoate; fluoro-cyclohexyl acetate; and fluoro-cyclohexanecarboxylic acid methyl ester; or an analog of any of the foregoing. 19.A composition comprising the product of claim
 17. 20. A method ofvisualization comprising: fluorinating a carbon containing compoundhaving an sp3 C—H bond by the method of claim 1, where the fluorinatingagent includes ¹⁸F and a product produced by the method includes ¹⁸F tocreate an imaging agent; administering the imaging agent to a patient;and performing positron emission tomography on the patient.
 21. Acomposition comprising at least two or more of a carbon containingcompound, a fluorinating agent, a fluorinating catalyst and an oxidant.22. A composition comprising a trans-difluoromanganese(IV) porphyrinMn^(IV)(TMP)F₂.
 23. A composition comprising a manganese complex havingat least one fluoride ligand bound to the manganese and the formulaL₅Mn(IV)—F, where L is selected from the group including oxygen,nitrogen, and halide, and the manganese has octahedral coordination withsix total ligands and a neutral overall charge.
 24. A compositioncomprising a manganese complex having at least one fluoride ligand boundto the manganese and the formula L₅Mn(V)—F, where L is selected from thegroup consisting of oxygen, nitrogen and halide, and the manganese hasoctahedral coordination with six total ligands and a neutral overallcharge.
 25. A composition comprising a manganese complex having one ortwo fluoride ligands bound to the manganese and the formula L₅Mn(IV)—For L₄Mn(IV)—F₂, where L is selected from the group consisting of oxygen,nitrogen and halide, and the manganese has octahedral coordination withsix total ligands and a neutral overall charge.
 26. A compositioncomprising a fluoro-buspirone.
 27. A composition comprising at least twoor more of a carbon containing compound having an sp3 C—H bond, afluorinating agent, a fluorinating catalyst, or an oxidant.
 28. Thecomposition of claim 27, wherein the carbon containing compound includesa compound selected from the group consisting of neopentane; toluene;cyclohexane; norcarane; trans-decalin; 5α-cholestane; sclareolide;1,3,5(10)-estratrien-17-one;(1R,4aS,8aS)-octahydro-5,5,8a-trimethyl-1-(3-oxobutyl)-naphtalenone;(1R,4S,6S,10S)-4,12,12-trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one;levomethorphan; lupine; 20-methyl-5alpha(H)-pregnane; isolongifolanone;caryophyllene acetate; N-acetyl-gabapentin methyl ester;acetyl-amantidine; phthalimido-amantadine; methyloctanoate; saturatedfatty acid esters; N-acetyl-Lyrica methyl ester; artemisinin, adapalene;finasteride; N-acetyl-methylphenidate; mecamylamine;N-acetyl-mecamylamine; N-acetyl-memantine; phthalimidi-memantine;N-acetyl-enanapril precursor methyl ester; progesterone; artemisinin;adapalene; dopamine derivative; pregabalin; cholestane; finasteride;methylphenidate derivative; mecamylamine; gabapentin; memantinederivative; gabapentin; rimantadine derivative; isoleucine derivative;leucine derivative; valine derivative; pregesterone; tramadol; enalaprilprecursor;(1R,4aS,8aS)-5,5,8a-trimethyl-1-(3-oxobutyl)octahydronaphthalen-2(1H)-one;phenylalanine; donepezil precursor; amphetamine; 6-tocopherol form ofvitamin E; tyrosine; melatonin; tryptophan; estrone acetate;progesterone; dopamine; homophenylalanine; DOPA; ibuprofen methyl ester;buspirone; eticyclidine; memantine; amantadine; lyrica; lubiprostone;penridopril; fosinopril; N-Phth amantadine; N-Phth Memantine;2-adamantanone; rimantadine analogue; adapalene precursor; perindoprilprecursor; protected gabapentin; methyl octanoate; methyl nonanate;methyl hexanoate; cyclohexyl acetate; and cyclohexane carboxylic acidmethyl ester; or an analog of any one of the foregoing.
 29. Thecomposition of claim 27, wherein the fluorinating agent is selected fromthe group consisting of silver (I) fluoride, silver (II) fluoride,tetrabutyl ammonium fluoride, sodium fluoride, potassium fluoride,silver fluoride and tetra alkyl ammonium fluoride, trialkyl aminetrihydrofluoride R₃N(HF)₃, the ammonium salt [R₃NH][H₂F₃] and potassiumcrown ether fluoride.
 30. The composition of claim 27, wherein thefluorinating catalyst includes a metal complexed with a ligand selectedfrom the group consisting of a porphyrin, a phthalocyanine, a corrole,an N-pyridylmethyl-tri-aza-cyclononane, an N,N-dipyridylmethylcyclohexadiamine, a tetra-aza-cyclotetra-decane, an N,N-dipyridylmethyl2,2′-dipyrrolidine, an N,N-dipyridylmethyl ethylenediamine, a tripyridylamine (TPA), a salen, a salophen, a phthalocyanine, and a porphyrazine.31. The composition of claim 30, wherein the metal is selected from thegroup consisting of manganese, copper, vanadium, chromium, iron, cobaltand nickel.
 32. The composition of claim 27, wherein the fluorinatingcatalyst is a manganese porphyrin, a manganese salen, or a manganesesalophen.
 33. The composition of claim 32, wherein the manganeseporphyrin is selected from the group consisting of Mn(TPP)Cl, Mn(TMP)Cl,Mn^(III)(TPP)C, Mn^(III)(TMP)Cl, Mn^(IV)(TMP)F₂,Mn(III)[tetra-2,6-dichlorophenyl porphyrin, Mn(III) [tetra-2-nitrophenylporphyrin], Mn(III) [tetra-2-naphthyl porphyrin, Mn(III)[pentachlorophenyl porphyrin, Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octachloroporphyrin], Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octabromoporphyrin], and Mn(III)[tetraphenyl-2,3,7,8,12,13,17,18-Octanitroporphyrin.
 34. The compositionof claim 27, wherein the fluorinating catalyst is a manganese complexhaving at least one fluoride ligand bound to the manganese and theformula L₅Mn(IV)—F, where L is selected from the group consisting ofoxygen, nitrogen, and halide, and the manganese has octahedralcoordination with six total ligands and a neutral overall charge. 35.The composition of claim 27, wherein the fluorinating catalyst is amanganese complex having at least one fluoride ligand bound to themanganese and the formula L₅Mn(V)—F, where L is selected from the groupconsisting of oxygen, nitrogen and halide, and the manganese hasoctahedral coordination with six total ligands and a neutral overallcharge.
 36. The composition of claim 27, wherein the fluorinatingcatalyst is a manganese complex having one or two fluoride ligands boundto the manganese and the formula L₅Mn(IV)—F or L₄Mn(IV)—F₂, where L isselected from the group consisting of oxygen, nitrogen and halide, andthe manganese has octahedral coordination with six total ligands and aneutral overall charge.
 37. The composition of claim 27, wherein theoxidant is selected from the group consisting ofmeta-chloroperoxybenzoic acid (mCPBA), idosylbenzene, peroxyacid, alkylperoxide, peroxy sulfate(oxone), peroxycarbonate, peroxyborate, iodosylmesitylene, pentafluoro-iodosylbenzene, benzene difluoroiodinane[phenyl-IF2], diacetoxyiodobenzene, 2-iodosylbenzoic acid, peroxyaceticacid, peroxyphthalic acid, and peroxytungstic acid.
 38. The compositionof claim 27, wherein the fluorinating agent includes ¹⁸F.
 39. A kitcomprising one or more container, wherein each container includes acomposition having at least one reactant for a fluorination reactionselected from the group consisting of a carbon containing compound, afluorinating agent, a fluorinating catalyst, and an oxidant, wherein thecomposition includes at least one fewer substance than required to makea fluorination reaction proceed.
 40. The kit of claim 39, furthercomprising a container having a solvent.
 41. The kit of claim 39,wherein the one or more containers in combination include all thesubstances required to make the fluorination reaction proceed.
 42. Thekit of claim 39, further comprising instructions for mixing thereactants from the at least one container.
 43. A composition comprisinga product of a method of direct oxidative C—H fluorination of a carboncontaining compound having an sp3 C—H bond comprising combining thecarbon containing compound, a fluorinating agent, a fluorinatingcatalyst, and an oxidant.
 44. The composition of claim 43, wherein thecarbon containing compound is neopentane; toluene; cyclohexane;norcarane; trans-decalin; 5α-cholestane; sclareolide; 1, 3,5(10)-estratrien-17-one;(1R,4aS,8aS)-octahydro-5,5,8a-trimethyl-1-(3-oxobutyl)-naphtalenone;(1R,4S,6S,10S)-4,12,12-trimethyl-tricyclo[8.2.0.04,6]dodecan-9-one;levomethorphan; lupine; 20-methyl-5alpha(H)-pregnane; isolongifolanone;caryophyllene acetate; N-acetyl-gabapentin methyl ester;acetyl-amantidine; phthalimido-amantadine; methyloctanoate; saturatedfatty acid esters; N-acetyl-Lyrica methyl ester; artemisinin, adapalene;finasteride; N-acetyl-methylphenidate; mecamylamine;N-acetyl-mecamylamine; N-acetyl-memantine; phthalimidi-memantine;N-acetyl-enanapril precursor methyl ester; progesterone; artemisinin;adapalene; dopamine derivative; pregabalin; cholestane; finasteride;methylphenidate derivative; mecamylamine; gabapentin; memantinederivative; gabapentin; rimantadine derivative; isoleucine derivative;leucine derivative; valine derivative; pregesterone; tramadol; enalaprilprecursor;(1R,4aS,8aS)-5,5,8a-trimethyl-1-(3-oxobutyl)octahydronaphthalen-2(1H)-one;phenylalanine; donepezil precursor; amphetamine; 6-tocopherol form ofvitamin E; tyrosine; melatonin; tryptophan; estrone acetate;progesterone; dopamine; homophenylalanine; DOPA; ibuprofen methyl ester;buspirone; eticyclidine; memantine; amantadine; lyrica; lubiprostone;penridopril; fosinopril; N-Phth amantadine; N-Phth Memantine;2-adamantanone; rimantadine analogue; adapalene precursor; perindoprilprecursor; protected gabapentin; methyl octanoate; methyl nonanate;methyl hexanoate; cyclohexyl acetate; and cyclohexane carboxylic acidmethyl ester; or an analog of any one of the foregoing.